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Background: Allogeneic haematopoietic stem cell transplantation (alloSCT) often remains the only curative therapy for hematologic malignancies. Although the management of transplant‐associated adverse events considerably improved over the last decades, nonrelapse mortality (NRM) remains a challenge, and endothelial dysfunction was identified as a major contributor to NRM. Methods: Statin‐based endothelial prophylaxis (SEP) has been implemented in the standard of care in our transplant centre to reduce NRM caused by endothelial injury. Here, we retrospectively analysed the impact of SEP on clinical outcome in a cohort of 347 alloSCT patients. Results: SEP (n = 209) was associated with significantly reduced NRM (hazard ratio 0.61, 95% CI 0.38–0.96) and better overall survival (OS) after acute graft‐versus‐host disease (HR 0.59, 95% CI 0.37–0.93). Subgroup analyses showed that the NRM benefit was mainly found in patients with an intermediate endothelial activation and stress index (EASIX), while relapse risk was not affected. On day 100 post‐alloSCT, patients receiving SEP had significantly higher levels of the rate‐limiting enzyme of tryptophan metabolism, indoleamine 2,3‐dioxygenase (IDO), higher kynurenine to tryptophan ratios as a proxy of IDO activity and tended to have lower levels of the endothelial injury marker ST2 (p =.055). No significant differences in interferon‐gamma or IL18 levels were observed. These biomarker signatures suggest that the beneficial effects of SEP might be mediated by both endothelial protection and immunomodulation. Conclusions: Together, these data suggest that SEP improves NRM and OS post‐alloSCT in particular in patients with intermediate endothelial risk and provide first mechanistic clues about its potential mode of action. [ABSTRACT FROM AUTHOR]

The article reports on a study which investigated the impact of telomere length on the outcome of allogeneic stem cell transplantation (SCT) for patients with poor risk chronic lymphocytic leukaemia (CLL) based on the German CLL3X trial which included 100 patients. Topics covered include association of telomere length with clinical characteristics, and analysis of telomere length using quantitative polymerase chain reaction.

The best approach for allogeneic haematopoietic stem cell transplantations (allo HCT) in patients with chronic lymphocytic leukaemia ( CLL) is unknown. We therefore analysed the impact of procedure- and centre-related factors on 5-year event-free survival ( EFS) in a large retrospective study. Data of 684 CLL patients who received a first allo HCT between 2000 and 2011 were analysed by multivariable Cox proportional hazards models with a frailty component to investigate unexplained centre heterogeneity. Five-year EFS of the whole cohort was 37% (95% confidence interval [ CI], 34-42%). Larger numbers of CLL allo HCTs (hazard ratio [ HR] 0·96, P = 0·002), certification of quality management ( HR 0·7, P = 0·045) and a higher gross national income per capita ( HR 0·4, P = 0·04) improved EFS. In vivo T-cell depletion ( TCD) with alemtuzumab compared to no TCD ( HR 1·5, P = 0·03), and a female donor compared to a male donor for a male patient ( HR 1·4, P = 0·02) had a negative impact on EFS, but not non-myeloablative versus more intensive conditioning. After correcting for patient-, procedure- and centre-characteristics, significant variation in centre outcomes persisted. In conclusion, further research on the impact of centre and procedural characteristics is warranted. Non-myeloablative conditioning appears to be the preferable approach for patients with CLL. [ABSTRACT FROM AUTHOR]

Weight loss and metabolic activity influence outcome after allogeneic stem cell transplantation (alloSCT). This study evaluates pre-conditioning Leptin, a peptide hormone involved in metabolism and immune homeostasis, as a prognostic factor for survival, relapse and non-relapse mortality (NRM) following alloSCT. Leptin serum levels prior to conditioning were determined in a cohort of patients transplanted for various hematologic malignancies (n = 524) and correlated retrospectively with clinical outcome. Findings related to patients with acute leukemia (AL) from this sample were validated in an independent cohort. Low pre-conditioning serum Leptin was an independent prognostic marker for increased risk of relapse (but not of NRM and overall mortality) following alloSCT for AL of intermediate and advanced stage (beyond first complete remission). Multivariate analysis revealed a hazard ratio (HR) for relapse of 0.75 per log2 increase (0.59–0.96, p = 0.020). This effect was similar in an independent validation cohort. Pre-conditioning serum Leptin was validated as a prognostic marker for early relapse by fitting the multivariate Cox model to the validation data. Pre-conditioning serum Leptin levels may serve as an independent prognostic marker for relapse following alloSCT in intermediate and advanced stage AL patients. Prospective studies are required to prove whether serum Leptin could be used for guiding nutritional intervention in patients with AL undergoing alloSCT. [ABSTRACT FROM AUTHOR]

The COVID-19 pandemic threatens patients with a compromised immune and endothelial system, including patients who underwent allogeneic stem cell transplantation (alloSCT). Thus, there is an unmet need for optimizing vaccination management in this high-risk cohort. Here, we monitored antibodies against SARS-CoV-2 spike protein (anti-S1) in 167 vaccinated alloSCT patients. Humoral immune responses were detectable in 81% of patients after two vaccinations with either mRNA-, vector-based, or heterologous regimens. Age, B-cell counts, time interval from vaccination, and the type of vaccine determined antibody titres in patients without systemic immunosuppression (sIS). Similar to a healthy control cohort, mRNA vaccine-based regimens induced higher titres than vector-based vaccines. Patients on two or more immunosuppressants rarely developed immunity. In contrast, 62% and 45% of patients without or on only one immunosuppressant, respectively, showed a strong humoral vaccination response (titre > 100). Exacerbation of cGVHD upon vaccination was observed in 6% of all patients and in 22% of patients receiving immunosuppression for cGVHD. cGVHD exacerbation and low antibody titres were both associated with higher angiopoietin-2 (ANG2) serum levels. In conclusion, mRNA-based vaccines elicit strong humoral responses in alloSCT patients in the absence of double sIS. Biomarkers such as ANG2 might help with weighing cGVHD risk versus beneficial responses. [ABSTRACT FROM AUTHOR]

BACKGROUND: Autologous stem cell transplantation (autoSCT) has improved the outcome of patients with mantle cell lymphoma (MCL) considerably. However, little is known about the patterns and outcome of MCL recurrence after autoSCT. METHODS: The authors conducted a retrospective study of 118 patients with MCL who underwent autoSCT from August 1992 to August 2008 at 3 different referral centers in Germany. RESULTS: Fifty-two relapses occurred for a cumulative incidence of 46% after 5 years. Only 3 patients relapsed after 5 years (at 90 months, 91 months, and 171 months) after undergoing autoSCT. A Cox regression analysis of the incidence of relapse identified not receiving rituximab before autoSCT and undergoing salvage autoSCT as predictive factors for relapse, whereas cytosine arabinoside intensification; a total body irradiation-based, high-dose regimen; patient age; and year of transplantation had no influence. The median overall survival (OS) after relapse was 23 months. Twenty patients (39%) underwent allogeneic stem cell transplantation (alloSCT) for relapse, and 11 of those patients remained in ongoing complete remission at the time of the current report. It is noteworthy that there were 4 long-term survivors who lived for >5 years after relapse even without undergoing alloSCT. A Cox regression analysis of OS after relapse revealed that the response duration after autoSCT was an adverse predictor of OS, whereas alloSCT was associated with a significantly longer OS after relapse. CONCLUSIONS: The current results indicated that autoSCT was capable of inducing long-term remission up to 16 years after treatment, but the outcome of patients with MCL who relapsed after autoSCT was poor, especially if their response duration after autoSCT was short. However, for a subset of patients with relapsed MCL, alloSCT may offer the possibility of durable survival, and individual patients can enjoy long-term survival after relapse even without undergoing alloSCT. [ABSTRACT FROM AUTHOR]

Pott C, Schrader C, Brüggemann M, Ritgen M, Harder L, Raff T, Tiemann M, Dreger P, Kneba M. Blastoid variant of mantle cell lymphoma: late progression from classical mantle cell lymphoma and quantitation of minimal residual disease.Eur J Haematol 2005: 74: 353–358.© Blackwell Munksgaard 2005.Objectives: Classical mantle cell lymphoma (MCL) and its blastoid variant (MCL-BV) are characterized by an extremely poor prognosis. Long-time survivors are rare, only very few patients with an overall survival over 10 years have been reported. We present a case of a 41-year-old male with a 12 yr history of MCL stage I to show, that very late relapses in MCL are possible and may present as a transformation into an aggressive blastoid variant and to illustrate the value of quantitative minimal residual disease (MRD) monitoring for treatment guidance.Methods: Diagnostic lymph node and bone marrow samples were investigated by immunohistochemistry. Clonality analysis was performed by immunoglobulin heavy chain gene(IGVH)and t(11;14) PCR. The MRD assessment was done by real-time quantitative PCR (RQ-PCR) on available follow-up samples.Results: By histologic review and sequencing of the clonalIGVHand t(11;14) PCR products we demonstrated a common clonal origin of the leucemic MCL-BV and the classical MCL diagnosed 12 yr earlier. Quantitative MRD assessment revealed significant MRD levels after intensive conventional chemotherapy including Rituximab. Therefore, treatment was early intensified by myeloablative radio-chemotherapy and allogeneic peripheral stem cell transplantation from an unrelated HLA-identical donor. This did not translate into a sustained remission as reflected by persisting MRD levels after transplantation and the patient died from rapid progressive disease 3.5 months after transplant.Conclusion: This report presents a rare case of long-term survivor of MCL with a progression of the original MCL cell clone to MCL-BV and demonstrates the clinical value of quantitative MRD assessment for optimized therapeutic management. [ABSTRACT FROM AUTHOR]

Simple Summary: We have previously shown that high pre-conditioning levels of Interleukin-18 were associated with worse survival after allogeneic stem cell transplantation due to increased non-relapse mortality. While no correlations with acute graft-versus-host disease were observed, interleukin-18-related excess mortality was mainly driven by fatal infectious complications. In multiple studies, delayed hematopoietic recovery and poor graft function following allogeneic stem cell transplantation has been demonstrated as a powerful predictor of non-relapse mortality. The present study links high interleukin-18 to delayed platelet recovery in allografted patients. Given the functions of interleukin-18 in regulating the quiescence of hematopoietic stem/progenitor cells, our findings may be explained by Interferon gamma-independent inhibitory effects of interleukin-18 on stem cell proliferation and hematopoietic reconstitution in allografted patients. Importantly, considering recent successful interleukin-18-neutralizing approaches in autoimmune disorders, our results provide a rationale to explore modulation of interleukin-18 for improving hematopoietic recovery and outcomes in allogeneic stem cell transplantation recipients. Interleukin-18 (IL-18) is an immunoregulatory cytokine and a context-dependent regulator of hematopoietic stem/progenitor cell (HSPC) quiescence in murine models. In a previous study, high pre-conditioning levels of IL-18 were associated with increased non-relapse mortality (NRM) after allogeneic stem cell transplantation (alloSCT). To investigate the clinical impact of IL-18 status on hematopoietic function, the associations of pre-conditioning and day 0–3 cytokine levels with platelet and neutrophil recovery were analyzed in a training cohort of 714 allografted patients. In adjusted logistic regression analyses, both increasing pre-conditioning and day 0–3 IL-18 levels had a significantly higher adjusted odds ratio (aOR) of delayed platelet and neutrophil recovery on day +28 post-transplant (aOR per two-fold increase: 1.6–2.0). The adverse impact of high pre-conditioning IL-18 on day +28 platelet recovery was verified in an independent cohort of 673 allografted patients (aOR per two-fold increase: 1.8 and 1.7 for total and free IL-18, respectively). In both cohorts, a platelet count ≤20/nL on day +28 was associated with a significantly increased hazard of NRM (hazard ratio 2.13 and 2.94, respectively). Our findings support the hypothesis that elevated peritransplant IL-18 levels affect post-transplant HSPC function and may provide a rationale to explore modulation of IL-18 for improving alloSCT outcomes. [ABSTRACT FROM AUTHOR]

Secondary acute myeloid leukemia (sAML) has been associated with inferior outcomes compared with de novo AML. Little is known about patient risk factors and outcomes in sAML after allogeneic hematopoietic stem cell transplantation (HCT); thus, this large systemic analysis of the European Society for Blood and Bone Marrow Transplantation registry was performed. This study included 4997 patients with sAML who received HCT from 2000 to 2016. In univariate analysis the 2-year cumulative incidence of chronic graft-versus-host disease (GVHD), relapse, and nonrelapse mortality (NRM) were 33.5% (95% confidence interval [CI], 32% to 34.9%), 33.7% (95% CI, 32.3% to 35.1%), and 27.5% (95% CI, 26.1% to 28.7%), respectively. Overall survival (OS), leukemia-free survival (LFS), and GVHD-free, relapse-free survival (GRFS) at 2 years were 44.5% (95% CI, 43% to 46%), 38.8% (95% CI, 37.4% to 40.3%), and 27.2% (95% CI, 25.9% to 28.6%), respectively. In multivariate analysis, patients receiving myeloablative regimens had decreased relapse (hazard ratio, .859; 95% CI, .761 to .97; P  = .01), higher NRM (hazard ratio, 1.175; 95% CI, 1.03 to 1.341; P  = .02), and no differences in OS, LFS, and GRFS compared with patients receiving reduced-intensity conditioning regimens. Active disease, adverse cytogenetics, older age, Karnofsky performance status (≤80%), ex vivo T cell depletion, other malignant hematologic diseases, and patient cytomegalovirus seropositivity were associated with inferior OS and LFS. These variables should be considered in patients with sAML in need of HCT, and further study regarding the impact of conditioning regimens on relapse is needed. [ABSTRACT FROM AUTHOR]

The aim of this retrospective study was to assess the safety and efficacy of bone marrow (BM) harvesting of allogeneic donors in an outpatient setting. Data of 226 related and unrelated donors who underwent BM harvest under general anesthesia at our institution from 2002 to 2014 were analyzed. Sixteen patients were a priori planned for admission for social reasons and 210 patients underwent BM harvesting with the intention to perform this procedure on an outpatient basis. To identify factors that predispose for hospital admission, we retrospectively analyzed donor characteristics and collection parameters. Outpatient treatment was performed in 178 of 210 donors (85%), whereas 32 donors (15%) required admission for clinical reasons (mainly clinically relevant anemia and circulatory problems). These individuals were not significantly different in sex distribution, age, donor's body weight, and the proportion of related donors from those who were not admitted. However, we found a significantly higher collection volume per kilogram donor's body weight in inpatients compared with volume for outpatients (16 versus 13 mL/kg body weight, P < .001). Severe adverse events or deaths occurred neither in the inpatient nor in the outpatient setting. Our study demonstrated that BM harvest in an outpatient setting is safe and feasible for the majority of allogeneic donors. A high volume of BM represented a major risk factor for inpatient admission. [ABSTRACT FROM AUTHOR]

Abstract: There is accumulating evidence indicating that endothelial factors are involved in the pathogenesis of GVHD. We have recently shown that steroid-refractory, but not sensitive, GVHD is characterized by higher pretransplantation serum levels of angiopoetin-2 (ANG2), a hormone mediating endothelial vulnerability. To evaluate whether endothelial vulnerability is a risk factor for GVHD per se or becomes important only when noticeable GVHD is established, we measured ANG2 along with additional serum markers of endothelial stress, including soluble thrombomodulin (sTM), IL-8 (CXCL8), and hepatocyte growth factor (HGF), in patients with no, low-grade, or severe GVHD. Patients with refractory GVHD exhibited elevated serum levels of ANG2, sTM, HGF, and IL-8 posttransplantation compared with patients with sensitive GVHD and patients without GVHD. Pretransplantation ANG2 was the only growth factor correlated with the risk of refractoriness and mortality, and then only within the subset of patients who developed grade III-IV GVHD. In contrast, ANG2 was not predictive of GVHD or nonrelapse mortality (NRM) in patients with no GVHD or low-grade GVHD. These findings provide evidence that endothelial function plays an important role in the pathogenesis of steroid refractoriness in ongoing GVHD; however, endothelial vulnerability does not predict incidence of GVHD. [Copyright &y& Elsevier]

Blastic plasmacytoid dendritic cell neoplasm (BPDC), formerly known as blastic NK cell lymphoma, is a rare hematopoietic malignancy preferentially involving skin, bone marrow, and lymph nodes. The overall prognosis of BPDC is dismal, with a median overall survival (OS) of only 12 to 14 months despite aggressive chemotherapy. Anecdotal reports suggest that younger patients might benefit from myeloablative therapy with autologous or allogeneic stem cell transplantation (alloSCT). However, with a median age at diagnosis beyond 60 years, BPDC primarily affects elderly patients. Here, we present for the first time evidence that also in elderly patients, alloSCT for BPDC is feasible and may result in sustained remission if conditioning with moderately reduced intensity is used. Between 2006 and 2009, 6 patients were treated at our institution who fulfilled the diagnostic criteria for BPDC. Median age was 67 (range: 55-80) years. All responded to acute leukemia-type induction therapy. Whereas 2 patients who were ineligible for alloSCT rapidly died of disease recurrence, 4 patients underwent alloSCT from unrelated donors as part of first-line (n = 1) or salvage treatment (n = 3). Two patients allografted in remission live disease free 57 and 16 months post-alloSCT, whereas 2 patients transplanted with active disease achieved complete remission but relapsed 6 and 18 months after transplantation, respectively. In conclusion, reduced-intensity conditioning (RIC) alloSCT from unrelated donors is feasible and seems to be effective in elderly patients with BPDC, suggesting that alloSCT should be pursued aggressively in patients with this otherwise fatal disease up to 70 years of age. [Copyright &y& Elsevier]

Relapse has become the major cause of treatment failure after allogeneic hematopoietic stem cell transplantation. Outcome of patients with clinical relapse after transplantation generally remains poor, but intervention prior to florid relapse improves outcome for certain hematologic malignancies. To detect early relapse or minimal residual disease, sensitive methods such as molecular genetics, tumor-specific molecular primers, fluorescence in situ hybridization (FISH), and multiparameter flow cytometry (MFC) are commonly used after allogeneic stem cell transplantation to monitor patients, but not all of them are included in the commonly employed disease-specific response criteria. The highest sensitivity and specificity can be achieved by molecular monitoring of tumor- or patient-specific markers measured by polymerase chain reaction-based techniques, but not all diseases have such targets for monitoring. Similar high sensitivity can be achieved by determination of recipient-donor chimerism, but its specificity regarding detection of relapse is low and differs substantially among diseases. Here, we summarize the current knowledge about the utilization of such sensitive monitoring techniques in chronic leukemias, myeloproliferative neoplasms, and lymphoid malignancies based on tumor-specific markers and cell chimerism and how these methods might augment the standard definitions of posttransplant remission, persistence, progression, relapse, and the prediction of relapse. Critically important is the need for standardization of the different residual disease techniques and to assess the clinical relevance of minimal residual disease and chimerism surveillance in individual diseases, which in turn must be followed by studies to assess the potential impact of specific interventional strategies. [Copyright &y& Elsevier]

Relapse has become the major cause of treatment failure after allogeneic stem cell transplantation. Outcome of patients with clinical relapse after transplantation generally remains poor, but intervention prior to florid relapse improves outcome for certain hematologic malignancies. To detect early relapse or minimal residual disease, sensitive methods such as molecular genetics, tumor-specific molecular primers, fluorescein in situ hybridization, and multiparameter flow cytometry (MFC) are commonly used after allogeneic stem cell transplantation to monitor patients, but not all of them are included in the commonly employed disease-specific response criteria. The highest sensitivity and specificity can be achieved by molecular monitoring of tumor- or patient-specific markers measured by polymerase chain reaction-based techniques, but not all diseases have such targets for monitoring. Similar high sensitivity can be achieved by determination of donor chimerism, but its specificity regarding detection of relapse is low and differs substantially among diseases. Here, we summarize the current knowledge about the utilization of such sensitive monitoring techniques based on tumor-specific markers and donor cell chimerism and how these methods might augment the standard definitions of posttransplant remission, persistence, progression, relapse, and the prediction of relapse. Critically important is the need for standardization of the different residual disease techniques and to assess the clinical relevance of minimal residual disease and chimerism surveillance in individual diseases, which in turn, must be followed by studies to assess the potential impact of specific interventional strategies. [ABSTRACT FROM AUTHOR]

Abstract: Transformed acute myeloid leukemia in myelofibrosis results in a median survival of less than 5 months. We identified 46 of 1048 myelofibrosis patients in the European Group for Blood and Marrow Transplantation registry who received allogeneic stem cell transplantation for acute leukemia evolving from myelofibrosis. The cumulative incidence of treatment-related mortality at 1 year was 28% (95% confidence interval, 14 to 42) and of relapse at 3 years was 47% (95% confidence interval, 31 to 63). The 3-year progression-free (PFS) and overall survival (OS) rates were 26% and 33%, respectively. The only significant factor for survival was complete remission versus no complete remission before transplantation (69% versus 22%, P = .008); however, complete remission was achieved only in 8 patients. Allogeneic stem cell transplantation can cure myelofibrosis patients transformed to leukemia. [Copyright &y& Elsevier]