Predicting sinusoidal obstruction syndrome after allogeneic stem cell transplantation with the EASIX biomarker panel

No biomarker panel is established for prediction of sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD), a major complication of allogeneic stem cell transplantation (alloSCT). We compared the potential of the Endothelial Activation and Stress Index (EASIX), based on lactate dehydrogenase, creatinine, and thrombocytes, with that of the SOS/VOD CIBMTR clinical risk score to predict SOS/VOD in two independent cohorts. In a third cohort, we studied the impact of endothelium-active prophylaxis with pravastatin and ursodeoxycholic acid (UDA) on SOS/VOD risk. The cumulative incidence of SOS/VOD within 28 days after alloSCT in the training cohort (Berlin, 2013-2015, n=446) and in the validation cohort (Heidelberg, 2002-2009, n=380) was 9.6% and 8.4%, respectively. In both cohorts, EASIX assessed at the day of alloSCT (EASIX-d0) was significantly associated with SOS/VOD incidence (p<0.0001), overall survival (OS) and non-relapse mortality (NRM). In contrast, the CIBMTR score showed no statistically significant association with SOS/VOD incidence, and did not predict OS and NRM. In patients receiving pravastatin/UDA, the cumulative incidence of SOS/VOD was significantly lower at 1.7% (p<0.0001, Heidelberg, 2010-2015, n=359) than in the two cohorts not receiving pravastatin/UDA. The protective effect was most pronounced in patients with high EASIX-d0. The cumulative SOS/VOD incidence in the highest EASIX-d0 quartiles were 18.1% and 16.8% in both cohorts without endothelial prophylaxis as compared to 2.2% in patients with pravastatin/UDA prophylaxis (p<0.0001). EASIX-d0 is the first validated biomarker for defining a subpopulation of alloSCT recipients at high risk for SOS/VOD. Statin/UDA endothelial prophylaxis could constitute a prophylactic measure for patients at increased SOS/VOD risk

Longitudinal fluorescence in situ hybridization reveals cytogenetic evolution in myeloma relapsing after autologous transplantation

To investigate cytogenetic evolution after upfront autologous stem cell transplantation for newly diagnosed myeloma we retrospectively analyzed fluorescence in situ hybridization results of 128 patients with paired bone marrow samples from the time of primary diagnosis and at relapse. High-risk cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more frequently after relapse (odds ratio: 6.33; 95% confidence interval: 1.86–33.42; P<0.001). No significant changes were observed for defined IGH translocations [t(4;14); t(11;14); t(14;16)] or hyperdiploid karyotypes between primary diagnosis and relapse. IGH translocations with unknown partners occurred more frequently at relapse. New deletion 17p and/or gain 1q21 were associated with cytogenetic heterogeneity, since some de novo lesions with different copy numbers were present only in subclones. No distinct baseline characteristics were associated with the occurrence of new high-risk cytogenetic abnormalities after progression. Patients who relapsed after novel agent-based induction therapy had an increased risk of developing high-risk aberrations (odds ratio 10.82; 95% confidence interval: 1.65–127.66; P=0.03) compared to those who were treated with conventional chemotherapy. Survival analysis revealed dismal outcomes regardless of whether high-risk aberrations were present at baseline (hazard ratio, 3.53; 95% confidence interval: 1.53–8.14; P=0.003) or developed at relapse only (hazard ratio, 3.06; 95% confidence interval: 1.09–8.59; P=0.03). Our results demonstrate cytogenetic evolution towards high-risk disease after autologous transplantation and underline the importance of repeated genetic testing in relapsed myeloma (EudraCT number of the HD4 trial: 2004-000944-26)

an interim analysis from the prospective GMMG-MM5 trial

We investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide, and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on data from relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients had been enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates of grade 2 or more peripheral neuropathy were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, P=0.001). Overall response rates were similar in patients treated intravenously or subcutaneously. The presence of International Staging System stage III disease, renal impairment or adverse cytogenetic abnormalities did not have a negative impact on overall response rates in either group. To our knowledge this is the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at eudract.ema.europa.eu as n. 2010-019173-16

Rationale and design of the German-speaking myeloma multicenter group (GMMG) trial HD6: a randomized phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma

Background: Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m2), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept. Methods: GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life. Results: Since this is the publication of a study protocol of an ongoing study, no results can be presented. Discussion: This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab. Trial registration: NCT02495922 on June 24th, 2015

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

Peer reviewe

Lichtheimia Infection in a Lymphoma Patient: Case Report and a Brief Review of the Available Diagnostic Tools

We describe the case of a patient with a T-lymphoblastic lymphoma whose disseminated mucormycosis was diagnosed with delay, and we address the diagnostic and therapeutic decision-making process and review the diagnostic workup of patients with potential IFD. The diagnosis was delayed despite a suggestive radiological presentation of the patient's pulmonary lesion. The uncommon risk profile (T-lymphoblastic lymphoma, short neutropenic phases) wrongly led to a low level of suspicion. The diagnosis was also hampered by the lack of indirect markers for infections caused by Mucorales, the low sensitivity of both fungal culture and panfungal PCR, and the limited availability of species-specific PCR. A high level of suspicion of IFD is needed, and aggressive diagnostic procedures should be promptly initiated even in apparently low-risk patients with uncommon presentations. The extent of the analytical workup should be decided on a case-by-case base. Diagnostic tests such as the galactomannan and β-D-glucan test and/or PCR on biological material followed by sequencing should be chosen according to their availability and after evaluation of their specificity and sensitivity. In high-risk patients, preemptive therapy with a broad-spectrum mould-active antifungal agent should be started before definitive diagnostic findings become available

Changes in treatment landscape of relapsed or refractory multiple myeloma and their association with mortality: Insights from German claims database

Objectives Emerging treatments for relapsed or refractory multiple myeloma (rrMM) have led to increasing options for many patients. This study aimed to assess changes in utilization of these options in Germany with a focus on modern triplet regimens including new agents, such as carfilzomib, ixazomib, elotuzumab and daratumumab, and to evaluate whether this had an impact on rrMM-related outcomes over time. Methods The study population consisted of 1255 rrMM patients who were assigned to one of the following 6 treatment groups: immunomodulatory drug (IMiD)-based doublets, proteasome inhibitor (PI)-based doublets, daratumumab monotherapy, PI-IMiD-based triplets, monoclonal antibodies (mAbs)-based triplets, or other treatment. Results Use of triplet-based therapy regimens increased from 5.9% in 2014 to 31.4% in 2017. In parallel, use of IMiD-based doublets decreased from 74.3% in 2014 to 37.6% in 2017. Over the same time period, the risk of death decreased by 32% and the risk of hospitalization which was reduced by 30%. The risk for serious adverse events remained unchanged. Conclusions Between 2014 and 2017, the use of triplet-based therapy regimens for rrMM in Germany has significantly increased and this was associated with a significant decline in deaths and hospitalizations without an increased incidence of serious adverse events