Low subcutaneous adipose tissue and myosteatosis are prognostic factors after allogeneic hematopoietic stem cell transplantation.

OBJECTIVE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for several hematological neoplasms. This study aimed to assess the parameters of body composition as predictors of post-transplant overall survival (OS) and adverse events in patients with leukemia, myelodysplastic syndromes (MDS), and myeloproliferative neoplasms (MPN). METHODS: This was a retrospective study of 122 adult patients who underwent their first allo-HSCT. The CT-based semi-automated measurement of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), visceral-to-subcutaneous fat ratio (VSR), sarcopenia in terms of skeletal muscle index (SMI), and myosteatosis based on the skeletal muscle radiation attenuation (SM-RA) was performed. Cox regression analysis was used to assess the association of body composition parameters with OS. RESULTS: In the univariate analysis, low SAT and myosteatosis were associated with lower OS (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.16-3.51, p = 0.01) and (HR 2.50, 95% CI 1.48-4.25, p =< 0.001), respectively. This association remained significant after adjusting for relevant covariates, with HR 2.32, 95% CI 1.23-4.38, p = 0.01 and HR 2.86, 95% CI 1.51-5.43, p =< 0.001, respectively. On the contrary, VAT, VSR, sarcopenia, and sarcopenic obesity were not statistically significant in OS. Severe post-transplant adverse events were more common in the low SAT group (odds ratio [OR] 3.12, 95% CI 1.32-7.40, p = 0.01) and OR 3.17, 95% CI 1.31-7.70, p =< 0.01 in the age- and sex-adjusted analysis. CONCLUSION: Low SAT and myosteatosis may contribute to an increased risk of post-transplant mortality, while low SAT appears to increase the risk of severe post-transplant adverse events.

Parameters of body composition do not predict survival in patients with multiple myeloma undergoing autologous stem cell transplantation.

Studies regarding the influence of body composition parameters as predictors on overall survival (OS) in patients with multiple myeloma (MM) are scarce. OS and progression-free survival (PFS) were retrospectively assessed in 129 patients with MM undergoing autologous stem cell transplantation (ASCT) after a follow-up of 2 years. A computed tomography (CT) based semi-automated assessment of body composition was performed. No statistically significant differences were noted in 2-year OS, PFS, or post-transplant adverse events in the body composition groups of subcutaneous adipose tissue (SAT) (low vs. high-SAT), visceral adipose tissue (VAT) (low vs. high-VAT), visceral-to-subcutaneous fat ratio (VSR) (low vs. high VSR), and sarcopenia in terms of skeletal muscle index (SMI) (non-sarcopenic vs. sarcopenic). In conclusion, adipose and muscle tissue do not limit OS or affect the PFS in patients with MM undergoing ASCT.

CT-defined sarcopenia predicts treatment response in primary central nervous system lymphomas.

OBJECTIVE: Body composition assessment derived from cross-sectional imaging has shown promising results as a prognostic biomarker in several tumor entities. Our aim was to analyze the role of low skeletal muscle mass (LSMM) and fat areas for prognosis of dose-limiting toxicity (DLT) and treatment response in patients with primary central nervous system lymphoma (PCNSL). METHODS: Overall, 61 patients (29 female patients, 47.5%) with a mean age of 63.8 ± 12.2 years, range 23-81 years, were identified in the data base between 2012 and 2020 with sufficient clinical and imaging data. Body composition assessment, comprising LSMM and visceral and subcutaneous fat areas, was performed on one axial slice on L3-height derived from staging computed tomography (CT) images. DLT was assessed during chemotherapy in clinical routine. Objective response rate (ORR) was measured on following magnetic resonance images of the head accordingly to the Cheson criteria. RESULTS: Twenty-eight patients had DLT (45.9%). Regression analysis revealed that LSMM was associated with objective response, OR = 5.19 (95% CI 1.35-19.94, p = 0.02) (univariable regression), and OR = 4.23 (95% CI 1.03- 17.38, p = 0.046) (multivariable regression). None of the body composition parameters could predict DLT. Patients with normal visceral to subcutaneous ratio (VSR) could be treated with more chemotherapy cycles compared to patients with high VSR (mean, 4.25 vs 2.94, p = 0.03). Patients with ORR had higher muscle density values compared to patients with stable and/or progressive disease (34.46 ± vs 28.18 ± HU, p = 0.02). CONCLUSIONS: LSMM is strongly associated with objective response in patients with PCNSL. Body composition parameters cannot predict DLT. CLINICAL RELEVANCE STATEMENT: Low skeletal muscle mass on computed tomography (CT) is an independent prognostic factor of poor treatment response in central nervous system lymphoma. Analysis of the skeletal musculature on staging CT should be implemented into the clinical routine in this tumor entity. KEY POINTS: • Low skeletal muscle mass is strongly associated with the objective response rate. • No body composition parameters could predict dose-limiting toxicity.

Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial.

BACKGROUND: Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). METHODS: Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 106 and 50 × 106 CARTs/m2. Leukapheresis, manufacturing and administration of CARTs were performed in-house. RESULTS: For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. CONCLUSION: In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www. CLINICALTRIALS: gov as NCT03676504.

Efficacy and safety of ruxolitinib in patients with newly-diagnosed polycythemia vera: futility analysis of the RuxoBEAT clinical trial of the GSG-MPN study group.

Patients (pts) with polycythemia vera (PV) suffer from pruritus, night sweats, and other symptoms, as well as from thromboembolic complications and progression to post-PV myelofibrosis. Ruxolitinib (RUX) is approved for second-line therapy in high-risk PV pts with hydroxyurea intolerance or resistance. The RuxoBEAT trial (NCT02577926, registered on October 1, 2015, at clinicaltrials.gov) is a multicenter, open-label, two-arm phase-IIb trial with a target population of 380 pts with PV or ET, randomized to receive RUX or best available therapy. This pre-specified futility analysis assesses the early clinical benefit and tolerability of RUX in previously untreated PV pts (6-week cytoreduction was allowed). Twenty-eight patients were randomly assigned to receive RUX. Compared to baseline, after 6 months of treatment, there was a significant reduction of median hematocrit (46 to 41%), the median number of phlebotomies per year (4.0 to 0), and median patient-reported pruritus scores (2 to 1), and a trend for reduced night sweat scores (1.5 to 0). JAK2V617F allele burden, as part of the scientific research program, also significantly decreased. One hundred nine adverse events (AEs) occurred in 24/28 patients (all grade 1 to 3), and no pt permanently discontinued treatment because of AEs. Thus, treatment with ruxolitinib in untreated PV pts is feasible, well-tolerated, and efficient regarding the above-mentioned endpoints.

Prognostic Impact of Quality and Distribution of Adipose Tissue in Patients With Primary Central Nervous System Lymphoma.

BACKGROUND/AIM: Body composition assessment has shown promising results as a prognostic biomarker as depicted by cross-sectional imaging of several tumor entities including lymphomas. The present study sought to elucidate the prognostic relevance of subcutaneous and visceral fat tissue (SAT and VAT) in patients with primary central nervous system lymphoma (PCNSL). PATIENTS AND METHODS: Overall, 74 patients (36 female patients, 46.7%) with a mean age of 64.2±12.8 years (range=23-81 years) were identified in the database with sufficient clinical and imaging data and included into this retrospective study. Fat area assessment was performed on one axial slide on L3-height derived from staging computed tomography (CT) images. Subcutaneous, visceral, and intramuscular adipose tissues (SAT, VAT, IMAT) were estimated. Also, density of SAT, VAT, and IMAT were estimated. Finally, the ratio VAT/SAT (VSR) was calculated. Overall and progression-free survival (OS and PFS) were used as study end points. RESULTS: In the observation period, overall, 47 patients (63.5%) died. Mean OS was 33.8±45.4 months and mean PFS was 26.6±42.7 months. The mean VAT value was 162±99.5 cm2, the mean SAT was 202.4±103.3 cm2, the mean VSR was 0.92±0.69. The hazard ratios (HRs) for overall survival were 0.87 for high VAT, 1.52 for SAT, and 0.73 for VSR in univariable analysis. For PFS it was 0.24 for VAT, 1.11 for SAT, and 1.07 for VSR. No values achieved statistical significance. Similar results were shown in Kaplan-Meier analysis for OS and PFS, respectively. CONCLUSION: Parameters of adipose tissue are not associated with OS and PFS in patients with PCNSL.

Sarcopenia does not predict outcome in patients with CNS lymphoma undergoing systemic therapy.

Low skeletal muscle mass as a proxy parameter for sarcopenia acts as a non-invasive imaging marker that is associated with poor prognosis in numerous types of cancer. The present study aimed to assess the influence of body composition parameters on overall survival (OS) and progression free survival (PFS) in patients diagnosed with primary central nervous system lymphoma (PCNSL). A total of 98 patients with PCNSL treated at University Hospital Magdeburg (Magdeburg, Germany) from 2013-2019 were retrospectively studied. Patients with a pre-treatment staging computed tomography (CT) scan that included the third lumbar vertebra were reviewed for analysis. Skeletal muscle area (SMA), skeletal muscle index (SMI), mean muscle density and skeletal muscle gauge (SMG) were measured on the CT scan prior to treatment. Parameters were associated with OS and PFS. Overall, 72 patients were included in the present study. Results of the present study demonstrated that the median OS was 10 months (range, 1-181 months), and 37 patients (51.4%) presented with sarcopenia. Moreover, the median OS was 7 months in the sarcopenic group and 32 months in the non-sarcopenic group. Results of the present study further illustrated that SMI, SMA, density and SMG did not exert a significant effect on OS. Notably, the median PFS was 2.5 months in the low SMI group and 10 months in the normal SMI group. Body composition parameters did not exert a significant effect on PFS. Overall, the results of the present study demonstrated that sarcopenia was not a risk factor for decreased OS or PFS in patients with PCNSL undergoing systemic treatment.

Kinetics of Renal Function during Induction in Newly Diagnosed Multiple Myeloma: Results of Two Prospective Studies by the German Myeloma Study Group DSMM.

BACKGROUND: Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) helps to prevent excess toxicity. Patients (pts) from two prospective trials were analyzed, provided postinduction (PInd) restaging was performed. Pts received three cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD) or btz, lenalidomide (len), and dex (VRd) or len, adriamycin, and dex (RAD). The minimum required estimated glomerular filtration rate (eGFR) was >30 mL/min. We analyzed the percent change of the renal function using the International Myeloma Working Group (IMWG) criteria and Kidney Disease: Improving Global Outcomes (KDIGO)-defined categories. RESULTS: Seven hundred and seventy-two patients were eligible. Three hundred and fifty-six received VCD, 214 VRd, and 202 RAD. VCD patients had the best baseline eGFR. The proportion of pts with eGFR <45 mL/min decreased from 7.3% at baseline to 1.9% PInd (p < 0.0001). Thirty-seven point one percent of VCD versus 49% of VRd patients had a decrease of GFR (p = 0.0872). IMWG-defined "renal complete response (CRrenal)" was achieved in 17/25 (68%) pts after VCD, 12/19 (63%) after RAD, and 14/27 (52%) after VRd (p = 0.4747). CONCLUSIONS: Analyzing a large and representative newly diagnosed myeloma (NDMM) group, we found no difference in CRrenal that occurred independently from the myeloma response across the three regimens. A trend towards deterioration of the renal function with VRd versus VCD may be explained by a better pretreatment "renal fitness" in the latter group.

Safety and efficacy of the combination of sonidegib and ruxolitinib in myelofibrosis: a phase 1b/2 dose-finding study.

The sonidegib and ruxolitinib combination was assessed in an open-label study in JAK inhibitor-naive patients with myelofibrosis (MF). The primary objective of phase 1b was to establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) and phase 2 was to assess spleen volume reduction at weeks 24 and 48. Fifty patients were enrolled. In the dose-escalation phase (n = 23), doses for sonidegib once daily/ruxolitinib twice daily were 400/10 mg (level 1, n = 8), 400/15 mg (level 2, n = 10), and 400/20 mg (level 3, n = 5). Two patients had dose-limiting toxicity at level 2: increased blood creatine phosphokinase (grades 3 and 4, n = 1 each). MTD/RP2D was determined as sonidegib 400 mg daily + ruxolitinib 20 mg twice daily. In phase 1b expansion and phase 2 stage 1 (n = 27), by weeks 24 and 48, ≥35% reduction in spleen volume was observed in 44.4% and 29.6% patients, respectively. By weeks 24 and 48, 42.0% and 26.0% patients had ≥50% reduction in Myelofibrosis Symptom Assessment Form total symptom score, respectively. Most common treatment-related adverse events (grade 3/4) were increased blood creatine phosphokinase (18%), anemia (14%), and thrombocytopenia (12%). Four deaths were reported due to multiple organ dysfunction syndrome (on-treatment; no relationship with study treatment), acute myeloid leukemia, MF progression, and aspiration pneumonia. Although well tolerated, this combination will not be further developed in MF patients due to modest overall benefit compared with historical ruxolitinib monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT01787552.

Correction: Frequency of infections in 948 MPN patients: a prospective multicenter patient-reported pilot study.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

JAK2-V617F promotes venous thrombosis through ß1/ß2 integrin activation.

JAK2-V617F-positive chronic myeloproliferative neoplasia (CMN) commonly displays dysfunction of integrins and adhesion molecules expressed on platelets, erythrocytes, and leukocytes. However, the mechanism by which the 2 major leukocyte integrin chains, ß1 and ß2, may contribute to CMN pathophysiology remained unclear. ß1 (α4ß1; VLA-4) and ß2 (αLß2; LFA-1) integrins are essential regulators for attachment of leukocytes to endothelial cells. We here showed enhanced adhesion of granulocytes from mice with JAK2-V617F knockin (JAK2+/VF mice) to vascular cell adhesion molecule 1- (VCAM1-) and intercellular adhesion molecule 1-coated (ICAM1-coated) surfaces. Soluble VCAM1 and ICAM1 ligand binding assays revealed increased affinity of ß1 and ß2 integrins for their respective ligands. For ß1 integrins, this correlated with a structural change from the low- to the high-affinity conformation induced by JAK2-V617F. JAK2-V617F triggered constitutive activation of the integrin inside-out signaling molecule Rap1, resulting in translocation toward the cell membrane. Employing a venous thrombosis model, we demonstrated that neutralizing anti-VLA-4 and anti-ß2 integrin antibodies suppress pathologic thrombosis as observed in JAK2+/VF mice. In addition, aberrant homing of JAK2+/VF leukocytes to the spleen was inhibited by neutralizing anti-ß2 antibodies and by pharmacologic inhibition of Rap1. Thus, our findings identified cross-talk between JAK2-V617F and integrin activation promoting pathologic thrombosis and abnormal trafficking of leukocytes to the spleen.

The cell fate determinant Scribble is required for maintenance of hematopoietic stem cell function.

Cell fate determinants influence self-renewal potential of hematopoietic stem cells. Scribble and Llgl1 belong to the Scribble polarity complex and reveal tumor-suppressor function in drosophila. In hematopoietic cells, genetic inactivation of Llgl1 leads to expansion of the stem cell pool and increases self-renewal capacity without conferring malignant transformation. Here we show that genetic inactivation of its putative complex partner Scribble results in functional impairment of hematopoietic stem cells (HSC) over serial transplantation and during stress. Although loss of Scribble deregulates transcriptional downstream effectors involved in stem cell proliferation, cell signaling, and cell motility, these effectors do not overlap with transcriptional targets of Llgl1. Binding partner analysis of Scribble in hematopoietic cells using affinity purification followed by mass spectometry confirms its role in cell signaling and motility but not for binding to polarity modules described in drosophila. Finally, requirement of Scribble for self-renewal capacity also affects leukemia stem cell function. Thus, Scribble is a regulator of adult HSCs, essential for maintenance of HSCs during phases of cell stress.

Mitochondrial BAX Determines the Predisposition to Apoptosis in Human AML.

Purpose: Cell-to-cell variability in apoptosis signaling contributes to heterogenic responses to cytotoxic stress in clinically heterogeneous neoplasia, such as acute myeloid leukemia (AML). The BCL-2 proteins BAX and BAK can commit mammalian cells to apoptosis and are inhibited by retrotranslocation from the mitochondria into the cytosol. The subcellular localization of BAX and BAK could determine the cellular predisposition to apoptotic death.Experimental Design: The relative localization of BAX and BAK was determined by fractionation of AML cell lines and patient samples of a test cohort and a validation cohort.Results: This study shows that relative BAX localization determines the predisposition of different AML cell lines to apoptosis. Human AML displays a surprising variety of relative BAX localizations. In a test cohort of 48 patients with AML, mitochondria-shifted BAX correlated with improved patient survival, FLT3-ITD status, and leukocytosis. Analysis of a validation cohort of 80 elderly patients treated with myelosuppressive chemotherapy confirmed that relative BAX localization correlates with probability of disease progression, FLT3-ITD status, and leukocytosis. Relative BAX localization could therefore be helpful to identify elderly or frail patients who may benefit from cytotoxic therapy.Conclusions: In this retrospective analysis of two independent AML cohorts, our data suggest that Bax localization may predict prognosis of patients with AML and cellular predisposition to apoptosis, combining the actual contribution of known and unknown factors to a final "common path." Clin Cancer Res; 23(16); 4805-16. ©2017 AACR.

Cell autonomous expression of CXCL-10 in JAK2V617F-mutated MPN.

PURPOSE: Myeloproliferative neoplasms (MPN) are clonal disorders of hematopoietic stem- and progenitor cells. Mutation of Janus-Kinase 2 (JAK2) is the most frequent genetic event detected in Philadelphia-negative MPN. In advanced phases, the clinical hallmark of the disease is a striking inflammatory syndrome. So far, the cellular and molecular basis of inflammation is not fully understood. We, therefore, sought to investigate the relationship of activating JAK2 mutation and aberrant cytokine expression in MPN. METHODS: Cytokine array was performed to identify Jak2V617F-related cytokine expression and secretion. CXCL10 mRNA expression was analyzed by qPCR in peripheral blood cells. To exclude paracrine/autocrine stimulation as a potential mechanism, we generated Ba/F3-EpoR-JAK2WT or EpoR-JAK2V617F cells lacking CXCL10 receptor. Pharmacologic inhibition of JAK2 kinase was achieved by JAK-Inhibitor treatment. Signaling pathways and downstream effectors were characterized by Western blotting, immunofluorescence microscopy, luciferase reporter assays, qPCR, and chromatin-immunoprecipitation studies. RESULTS: We identified CXCL10 as the most highly induced cytokine in JAK2-mutated cell lines. In MPN patients, CXCL10 is highly expressed in JAK2V617F but not JAK2WT MPN or healthy donor controls. Moreover, CXCL10 expression correlates with JAK2V617F allelic burden. High CXCL10 correlates with the presence of clinical risk factors but not with clinical symptoms and quality of life. Pharmacologic inhibition of mutated JAK2 kinase inhibits CXCL10 expression. NFκB signaling is activated downstream of JAK2V617F receptor and directly induces CXCL10 expression. CONCLUSIONS: Our data provide first evidence for a link between oncogenic JAK2V617F signaling and cell intrinsic induction of CXCL10 induced by activated NFkB signaling.

Characteristics and treatment of polycythemia vera patients in clinical practice: a multicenter chart review on 1476 individuals in Germany.

PURPOSE: Treatment recommendations for patients with polycythemia vera (PV) are well established. Most multicenter trials investigating novel therapeutic strategies for PV are developed and conducted at university hospitals and specialized academic centers. The majority of patients in Germany, however, are treated in an outpatient (ambulatory) setting. The aim of this study was to evaluate the 'real-life' situation in a cohort of 1467 patients by analyzing data from a survey conducted at private practices and primary care centers. METHODS: Eligible private practices and primary care centers treating patients with MPN were recruited to participate in a paper-pencil-based survey conducted from March 2015 until March 2016 in Germany. Hematologists were asked to report from patient charts. Descriptive analyses were conducted to assess for outcomes examined by reported prognostic risk scores, symptom scores and clinical response criteria. RESULTS: In total, 34 centers participated in our retrospective survey and provided data on 1476 patients. Most patients were of older age (66.7 % older than 66 years of age), which was the main risk factor according to the criteria published by Tefferi and colleagues. Molecular status at diagnosis was not evaluated in 23 % of patients. Low rates of constitutional symptoms were reported in this physician-based survey with concentration problems, fatigue and itching being the main PV-related symptoms. Phlebotomy and hydroxyurea were the main cytoreductive measures for hematocrit control. The majority of patients were responsive (67.8 %) and tolerant (77.3 %) to hydroxyurea therapy. Interferon and JAK inhibitor therapy were used in <10 % of patients, respectively. Overall, leukocytosis, thrombocytosis and hematocrit could be effectively controlled by any therapy applied. Lack of efficacy was reported on reduction of constitutional symptoms and splenomegaly. CONCLUSIONS: The patient population investigated was older than participants in published large multicenter trials. The majority of patients were categorized as 'high risk.' Age was the main risk factor. Molecular status was unavailable in the majority of patients diagnosed prior to 2008. The physician-based survey reported on significantly lower rates of constitutional symptoms than patient-based surveys in the literature. Consistent with previously published reports, hydroxyurea is the main agent used for PV therapy in an outpatient setting resulting in efficient control of hematopoietic parameters. Constitutional symptoms and splenomegaly, however, may not be reduced efficiently, which could be improved by the use of JAK inhibitor treatment for high-risk patients in the future.