BACKGROUND:Few studies examined treatment-specific long-term risks of cardiovascular diseases (CVD) in diffuse large B-cell lymphoma survivors treated with potentially cardiotoxic radiotherapy and/or chemotherapy with or without rituximab after the 1990s. METHODS:Long-term CVD risk was examined in a multicenter cohort comprising 2356 diffuse large B-cell lymphoma survivors who survived at least 5 years and who were treated at ages 15-61 years in 1989-2012. CVD data were acquired from medical records, general practitioners, and disease registries. Observed CVD numbers were compared with expected CVD incidence in the Dutch population to estimate standardized incidence ratios (SIRs) and absolute excess risks (10 000 person-years). Treatment-specific CVD risks were assessed using multivariable Cox regression. RESULTS:During a median follow-up of 14.2 years (IQR = 10.1-18.9 years), 312 survivors were diagnosed with a first CVD at least 5 years after treatment. Compared with the general population, diffuse large B-cell lymphoma survivors had increased risks of heart failure ([HF]; SIR = 3.9, 95% confidence interval [CI] = 3.4 to 4.6; absolute excess risk = 62.8) and cerebrovascular accident (SIR = 1.3, 95% CI = 1.0 to 1.7; absolute excess risk = 9.8), while risk of coronary artery disease was decreased (SIR = 0.7, 95% CI = 0.5 to 0.9; absolute excess risk = -30.9). HF risk was higher among females (SIR = 5.3, 95% CI = 4.2 to 6.5) than males (SIR = 3.2, 95% CI = 2.6 to 4.0, P for heterogeneity < .001), and among survivors aged 40 years and younger at diffuse large B-cell lymphoma treatment (SIR = 10.5, 95% CI = 7.2 to 14.8; P for trend < .001). Exposure to more than 300 mg/m2 doxorubicin was associated with a 2.8-fold (95% CI = 1.7 to 4.5) increased risk of cardiomyopathy or HF, while radiotherapy involving the heart was associated with a 1.9-fold (95% CI = 1.1 to 3.1) increased risk of valvular heart disease. CONCLUSION:Those surviving at least 5 years after diffuse large B-cell lymphoma have increased risks of developing CVDs, especially HF. Physicians and patients should recognize this risk, and individualized cardiac screening should be considered.

Curative-intent immunochemotherapy fails in ∼30% of patients with large B cell lymphoma (LBCL), yet no validated molecular tool enables early identification of high-risk individuals to guide treatment intensification. Using shallow whole-genome sequencing (sWGS) of plasma cell-free DNA from 190 LBCL patients, we develop and validate the ACT score (aberrations, composition of fragments, and terminal motif analyses), a composite classifier integrating genomic and fragmentomic features from a single post-cycle-1 sample. ACT-positive patients have worse 2-year outcomes versus ACT-negative patients: time-to-progression 29% vs. 83% (hazard ratio [HR]: 4.4, 95% confidence interval [CI]: 1.9-10.0; p = 1.5 × 10-4) and overall survival 47% vs. 93% (HR: 8.7, 95% CI: 3.0-25.4; p = 1.8 × 10-6). The ACT score is independently prognostic of the International Prognostic Index, and their combination identifies the highest risk patients. Unlike mutation-based approaches, this assay requires neither tumor tissue, germline control, nor a baseline plasma sample. Built on open-source tools and sWGS, the ACT score offers a feasible, scalable strategy for early risk stratification in aggressive LBCL.

BACKGROUND:Patients with Hodgkin lymphoma are at increased risk of developing lung cancer, especially after chest radiation therapy. No tools are currently available, however, to predict lung cancer risk for different Hodgkin lymphoma treatments. METHODS:In a cohort of 5370 individuals who had survived Hodgkin lymphoma for at least 5 years, were 15 to 50 years of age at the time of Hodgkin lymphoma diagnosis, and who were treated in the Netherlands between 1965 and 2012, we used radiation therapy fields and prescribed dose to estimate mean lung dose. The twinning method was used to divide the cohort into homogenous parts: 80% for model development and 20% for validation using inverse probability of censoring weighting area under the curve. Cox proportional hazards models allowing for time-dependent coefficients were used to model time from Hodgkin lymphoma diagnosis to lung cancer and lung cancer-free death as the competing event for predicting absolute lung cancer risk up to 30 years after Hodgkin lymphoma diagnosis. RESULTS:Treatment information consisted of supradiaphragmatic radiation therapy in 75.2% of patients with a mean lung dose of 15.8 Gy. During follow-up, 218 survivors developed lung cancer. Older age, male sex, smoking at the time of Hodgkin lymphoma diagnosis, and higher mean lung dose were associated with higher lung cancer risk. The median Inter Quartile Range (IQR) estimated 30-year absolute lung cancer risk in our cohort was 1.2% (0.8%-1.9%) in nonsmokers and 6.9% (4.6%-10.9%) in smokers at the time of Hodgkin lymphoma diagnosis. The 20-year and 30-year inverse probability of censoring weighting areas under the curve values were 0.79 (95% Confidence Interval (CI) = 0.73 to 0.85) and 0.75 (95% CI = 0.69 to 0.81), respectively. CONCLUSION:We developed a well-calibrated prediction tool that estimates long-term risk of lung cancer with good discrimination based on patient characteristics and mean lung dose, allowing application in Hodgkin lymphoma survivors and contemporary patients with Hodgkin lymphoma.

BACKGROUND & AIMS:Medical nutrition therapy (MNT) is commonly used in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing intensive remission-induction treatment to prevent malnutrition, particularly the loss of fat-free mass (FFM)/muscle mass, as well as associated adverse outcomes. However, studies examining the associations of proactive versus wait-and-see approaches toward MNT with nutritional, physical, and clinical outcomes in these patients are lacking. Therefore, this study aimed to explore the associations of these different MNT approaches with body composition changes, as well as physical and clinical outcomes in AML/MDS patients undergoing intensive remission-induction treatment. Additionally, the study aimed to explore the relationships between body composition changes and physical and clinical outcomes, and whether these associations varied between the proactive and wait-and-see strategies. METHODS:In this multicenter prospective correlational study, newly diagnosed AML/MDS patients undergoing intensive remission-induction treatment were included. Patients were treated in one of five hospitals using a proactive approach toward MNT, initiating MNT when nutritional intake became inadequate, or in the single hospital in the Netherlands that followed a wait-and-see strategy, limiting the use of MNT to exceptional and severe cases only. Body composition was assessed at the start of treatment, weekly during admission and at discharge, and handgrip strength, and patient-reported physical functioning and fatigue at treatment initiation and discharge. Information on number of complications, and duration of fever and hospital length of stay (LOS) was collected from medical records. Within-group changes in body composition and between-group differences were tested using paired or independent t, Wilcoxon signed-rank or two-sample tests, respectively, or chi-square/Fisher's exact tests for proportions. The longitudinal patterns between proactive MNT approach/wait-and-see strategy hospitals were compared by means of linear mixed effects models. Associations between body composition changes and physical and clinical outcomes were explored using multiple linear regression models, and compared between proactive MNT approach/wait-and-see strategy hospitals. RESULTS:In this study, 204 AML/MDS patients (54 % male, mean age: 56.3 ± 13.0 years) were included, of whom 140 underwent treatment in a hospital using a proactive approach toward MNT and 64 in the hospital following a wait-and-see strategy. In the proactive MNT approach hospitals, 57 % of patients received MNT during the first chemotherapy cycle versus 8 % of patients in the wait-and-see hospital (p < 0.0001). Both approaches toward MNT were associated with significant decreases in body weight, FFM/muscle mass, and muscle strength. However, losses in FFM/muscle mass and muscle strength did not differ significantly between the strategies, while body weight loss was lower with the proactive approach (estimated between-group difference during the first cycle: 0.44 kg/week (95 % CI 0.18-0.70 kg/week, p = 0.0008), primarily due to better preservation of fat mass (FM) (p < 0.05). Additionally, the proactive MNT strategy was associated with fewer nutrition impact symptoms (p < 0.0001), fewer complications (p = 0.01), and shorter LOS (33 days (IQR: 27-41) vs 29 days (IQR: 26-34), p = 0.009). Similar results were observed during the second chemotherapy cycle. Furthermore, better maintenance of body weight and indicators of FFM/muscle mass and FM were significantly associated with shorter LOS and fever duration, fewer complications, improved physical functioning and/or reduced fatigue. Several associations differed significantly between the two MNT strategies, given that decreased body composition parameters were associated with worse physical and clinical outcomes in the wait-and-see hospital, while in the proactive MNT approach hospitals these associations were opposite or attenuated and non-significant. CONCLUSION:In AML/MDS patients undergoing intensive remission-induction treatment, a proactive approach toward MNT should be used, as it was associated with fewer nutrition impact symptoms, fewer complications, shorter LOS, and better body weight maintenance, mainly through better preservation of FM, compared to a wait-and-see strategy. Maintenance of body weight, FFM/muscle mass and/or FM was associated with improved physical and clinical outcomes. Given that proactive use of MNT could not prevent loss of FFM/muscle mass and muscle strength, future research should focus on combined nutritional and physical exercise interventions aimed at reducing these losses.

7000 Background: The prognostic utility of circulating tumor DNA measurable residual disease (ctDNA-MRD) detection at end of treatment (EOT) using phased variant (PV) enrichment and detection sequencing (PhasED-Seq) has been demonstrated in patients with diffuse large B-cell lymphoma (DLBCL) receiving first-line (1L) therapy. Prior studies are limited by treatment, patient, and sample heterogeneity. Here, we independently validate the prognostic value of PhasED-Seq in a national, multi-center study of uniformly treated 1L DLBCL patients. Methods: ctDNA-MRD was assessed using Foresight CLARITY in LBCL patients enrolled on HOVON-902 from >50 centers in the Netherlands and Belgium. Patients were treated with curative-intent 1L therapy (R-CHOP or DA-EPOCH-R). We evaluated the prognostic significance of MRD status [positive (+), negative (-)] on progression-free survival (PFS) and overall survival (OS). PVs were identified from pretreatment biopsies or plasma with matched normal DNA. EOT plasma samples were used for ctDNA-MRD detection. Results: A total of 150 of 156 (96%) eligible patients had successful PV identification. Of included patients, 90%, 9%, and 1% had DLBCL, HGBL, and PBMCL, respectively. IPI distribution was 22% low, 29% low-intermediate, 27% high-intermediate, and 22% high risk; median age was 67.5. The 24-month PFS and OS in this cohort were 74% and 86%, respectively, with 31 months of median follow-up. At the EOT, 76% of patients were MRD- and 24% were MRD+. MRD+ status significantly predicted inferior PFS (2 yr PFS 88 vs 28%; HR 9.7, 95% CI 4.2-22.3, p<0.0001) and OS (2 yr OS 97 vs 50%; HR 10.6, 95% CI 4.1-27.7, p<0.0001). Moreover, in patients without complete response, MRD+ was significantly prognostic for PFS, suggesting an ability to adjudicate imaging results (HR for PFS 7.6, 95% CI 3.6-16.3, p < 0.0001). Among patients who were MRD- and achieved CMR at EOT, 2-year PFS and OS were 91% and 99%, respectively. All patients who failed to achieve CMR and remained MRD+ experienced relapse. ctDNA-MRD was prognostic for outcomes in all subgroups considered, including source of baseline sample (tumor versus plasma), best clinical response, IPI, sex, lactate dehydrogenase, stage, or extranodal disease. In multivariate analysis including ctDNA-MRD, IPI, and best overall response, ctDNA-MRD was significantly and independently prognostic for both PFS [HR for ctDNA: 7.1, 95% CI 3.5-14.3, p<0.0001] and OS [HR for ctDNA: 5.1, 95% CI 2.2-11.9, p=0.00018]. Conclusions: We validated the prognostic value of PhasED-Seq-based ctDNA-MRD in a real-world multicenter 1L DLBCL cohort. This highlights the utility of ctDNA-MRD to confirm residual disease in patients without complete response by imaging, as well as the potential to identify patients who may benefit from consolidation therapy. These results support the integration of MRD as a standard component of response evaluation in 1L DLBCL treatment.

PURPOSE:Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy (RT) at a young age have a strongly increased risk of breast cancer (BC). Studies in childhood cancer survivors have shown that doxorubicin exposure may also increase BC risk. Although doxorubicin is the cornerstone of HL chemotherapy, the association between doxorubicin and BC risk has not been examined in HL survivors treated at adult ages. METHODS:We assessed BC risk in a cohort of 1,964 female 5-year HL survivors, treated at age 15-50 years in 20 Dutch hospitals between 1975 and 2008. We calculated standardized incidence ratios, absolute excess risks, and cumulative incidences. Doxorubicin exposure was analyzed using multivariable Cox regression analyses. RESULTS:After a median follow-up of 21.6 years (IQR, 15.8-27.1 years), 252 women had developed invasive BC or ductal carcinoma in situ. The 30-year cumulative incidence was 20.8% (95% CI, 18.2 to 23.4). Survivors treated with a cumulative doxorubicin dose of >200 mg/m2 had a 1.5-fold increased BC risk (95% CI, 1.08 to 2.1), compared with survivors not treated with doxorubicin. BC risk increased 1.18-fold (95% CI, 1.05 to 1.32) per additional 100 mg/m2 doxorubicin (Ptrend = .004). The risk increase associated with doxorubicin (yes v no) was not modified by age at first treatment (hazard ratio [HR]age <21 years, 1.5 [95% CI, 0.9 to 2.6]; HRage ≥21 years, 1.3 [95% CI, 0.9 to 1.9) or chest RT (HRwithout mantle/axillary field RT, 1.9 [95% CI, 1.06 to 3.3]; HRwith mantle/axillary field RT, 1.2 [95% CI, 0.8 to 1.8]). CONCLUSION:This study shows that treatment with doxorubicin is associated with increased BC risk in both adolescent and adult HL survivors. Our results have implications for BC surveillance guidelines for HL survivors and treatment strategies for patients with newly diagnosed HL.

Background/Objectives: Patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) often receive medical nutrition therapy (MNT) during intensive remission-induction treatment. Since little is known about changes in nutritional status, specifically body composition, in this patient population, these changes and their associations with physical and clinical outcomes were assessed. Subjects/Methods: In this multicenter prospective observational study, newly diagnosed AML/MDS patients who received intensive remission-induction chemotherapy, routine dietary counseling by a dietician and MNT immediately upon inadequate nutritional intake, were included. At treatment initiation and discharge, nutritional status, including Patient-Generated Subjective Global Assessment (PG-SGA)-scores and body composition, physical outcomes and fatigue were assessed. Associations of nutritional status/body composition with physical outcomes, fatigue, fever duration, number of complications, time to neutrophil engraftment and hospital length of stay (LOS) (collected from medical records) were examined using multiple regression analysis. Results: In >91% of the 126 AML/MDS patients included, nutritional intake was adequate, with 61% receiving MNT. Nevertheless, body weight decreased significantly (p < 0.001) and mainly consisted of a loss of muscle/fat-free mass (FFM) (p < 0.001), while fat mass (FM) remained unchanged (p-value range = 0.71-0.77). Body weight and waist circumference showed significant negative associations with fever duration and/or number of complications. Significant positive associations were found between mid-upper arm muscle circumference (MUAMC) and physical functioning and between PG-SGA-scores and fatigue. Body weight and MUAMC were also negatively associated with LOS. Conclusion: Despite MNT in AML/MDS patients undergoing intensive chemotherapy, muscle/FFM decreased while FM remained unchanged. Maintenance of nutritional status was associated with improved physical and clinical outcomes.

The HOVON 104 studied bortezomib-dexamethasone induction therapy and autologous stem cell transplantation in 50 patients, of whom 35 received an autologous stem cell transplantation (ASCT). We demonstrate a 5-year overall survival (OS) of 73% and progression-free survival (PFS) of 52% for all 50 patients with a median follow-up of 61.3 months. For the 35 transplanted patients, calculated from the date of ASCT, the 5-year OS and PFS were 91% and 68%, respectively. After ASCT, the rate of organ response improved over time but stabilized around 3 years. A complete cardiac response was seen in around 60% of patients and remained stable from 2 years onward. Reaching complete renal response was slower over time and achieved by 61% of the renal-affected patients at 5 years. We confirm the excellent outcomes after ASCT and demonstrate a 60% complete organ response with longer follow-up.

Background The MYC oncogene exerts numerous tumor-promoting functions and may enable anti-tumor immune escape by contributing to the remodeling of the tumor microenvironment (TME, PMID 33081056). In light of the development of novel immunotherapies for lymphomas, we compared the TME composition of MYC-rearranged (MYC-R) high-grade B-cell lymphomas (HGBL) to ‘MYC negative’ diffuse large B-cell lymphomas, not otherwise specified (DLBCL) at DNA, RNA and protein levels. Methods Biopsy specimens from HGBL patients (HOVON-152 trial, NCT03620578) and DLBCL (HOVON-902 cohort, NCT04139252) were selected based on sample availability. MYC-R, BCL2-R and BCL6-R were determined using fluorescence in situ hybridization (FISH), using break-apart probes according to standard diagnostic lymphoma work up. We performed genomic profiling (targeted next-generation sequencing (tNGS), lon Torrent; n=36 HGBL/26 DLBCL) using the validated AmpliSeq BLYMFv2 panel, gene-expression profiling (GEP, NanoString; n=53/80) using the BLYMF777 probe set as previously described (PMID 34478526/35454765), and imaging mass cytometry (IMC, Hyperion; n=40/32) using a 41 antibody-marker panel for phenotyping to define the molecular landscape of tumors and determine the composition of their TME. Statistical differences between abundances were determined using the Fisher's exact test and Student's t-test. Results The majority of HGBL cases exhibited recurrent BLC2 rearrangements: 66% of cases in the genomic profiling and GEP cohorts and 62,5% in the IMC cohort were classified as ‘BCL2 double hit (DH)‘. BCL6 DH was observed in 11-15% of HGBL cases. Additionally, 21-22% of all HGBL cases had MYC, BCL2 and BCL6 rearrangements and were classified as triple hit. MYC-R were absent in all DLBCL cases. DNA: genomic profiling Consistent with previous literature, chromatin modifiers CREBBP and KMT2D were frequently mutated in HGBL as well as in DLBCL. Notably, HGBL had more mutations in TNFRSF14 (HVEM, p=0.007), BCL6 (p=0.01), and B-cell transcription factor IRF8 (p=0.04), while DLBCL showed higher frequencies of mutations in ZEB2 (p=0.01), KLHL6, GRHPR, IRF4 (all p=0.03) and tumor suppressor BTG2 (p=0.05), indicating distinct mutational profiles outside previously defined genetic subgroups (PMID 29713087/29641966). RNA: GEP signatures The majority of both HGBL and DLBCL cases were found to be GCB according to COO (Lymph2Cx). Despite mutational differences between the cohorts, GEP revealed a higher expression of genes related to the dark zone signature (DZsig, PMID 36302166/37552496) and MYC activity (PMID 27923830) in HGBL, while these genes were expressed at low levels in DLBCL. Protein: IMC phenotypes Using IMC we determined the composition of TME immune phenotypes in four cellular compartments: tumor, lymphoid, myeloid and stromal cells. In total, 666.809 cells (range 3-18K per patient) were obtained and 131 unique cellular phenotypes were defined. Clustering IMC phenotypes revealed three TME types: lymphoid immune-rich (mainly DLBCL cases), lymphoid immune-depleted (largely HGBL cases), and intermediate (including both DLBCL and HGBL). In detail, HGBL cases exhibited lower percentages of lymphoid cells (p<0.001) and were depleted for CD8+ T-cells, including naïve, effector memory and central memory CD8+ cytotoxic T-cells (all p<0.001), suggesting an immunosuppressed microenvironment. The amount of FOXP3+ T-cells (p=0.04), γδ-T-cells (p=0.03), and innate (like) lymphocytes (p<0.001) was also decreased in HGBL as compared to DLBCL. The TME of HGBL was significantly depleted in (proinflammatory) monocytes (p<0.04) and PD-L1+ macrophages (p<0.001), while there was a trend toward lower percentages of total myeloid cells in HGBL (p=0.07). Tumor and stromal cell percentages were similar between both groups (p=0.3). Conclusion This large comparison of MYC-R HGBL versus ‘MYC negative’ DLBCL cases using multi-omic analysis revealed a distinct TME in HGBL patients with increased frequencies of mutations in B-cell transcription factors, an abundance of discriminative MYC-related gene-expression signatures and, most strikingly, significantly lower infiltration of immune cells, especially cytotoxic T-cells, as compared to DLBCL. This suggests that MYC is linked to an immune-suppressed TME. These differences should be taken into account when developing T-cell engaging therapies for optimal efficacy.

Patients with high-grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBL- MYC/BCL2 ) respond poorly to immunochemotherapy compared with patients with diffuse large B-cell lymphoma not otherwise speci fied (DLBCL NOS) without a MYC rearrangement. This suggests a negative impact of lymphoma-intrinsic MYC on the immune system. To investigate this, we compared circulating T cells and natural killer (NK) cells of patients with HGBLMYC/BCL2 (n = 66), patients with DLBCL NOS (n = 53), and age-matched healthy donors (HDs; n = 16) by flow cytometry and performed proliferation, cytokine production, and cytotoxicity assays. Compared with HDs, both lymphoma subtypes displayed similar frequencies of CD8 + T cells but decreased CD4 + T cells. Regulatory T-cell (Treg) frequencies were reduced only in patients with DLBCL NOS. Activated (HLA-DR + / CD38 + ) T cells, PD-1 + CD4 + T cells, and PD-1 + Tregs were increased in both lymphoma subtypes, but PD-1 + CD8 + T cells were increased only in HGBLMYC/BCL2. Patients with DLBCL NOS, but not patients with HGBLMYC/BCL2 , exhibited higher frequencies of senescent T cells than HDs. Functional assays showed no overt differences between both lymphoma groups and HDs. Deeper analyses revealed that PD-1 + T cells of patients with HGBLMYC/BCL2 were exhausted with impaired cytokine production and degranulation. Patients with DLBCL NOS, but not patients with HGBLMYC/BCL2 , exhibited higher frequencies of NK cells expressing inhibiting receptor NKG2A. Both lymphoma subtypes exhibited lower TIM -3 + - and DNAM-1 + -expressing NK cells. Although NK cells of patients with HGBLMYC/BCL2 showed less degranulation, they were not defective in cytotoxicity. In conclusion, our results demonstrate an increased exhaustion in circulating T cells of patients with HGBLMYC/BCL2 . Nonetheless, the overall intact peripheral T-cell and NK-cell functions in these patients emphasize the importance of investigating potential immune evasion in the microenvironment of MYC -rearranged lymphomas.

Background:Multiple myeloma (MM) is a hematologic malignancy, characterized by clonal proliferation of plasma cells in the bone marrow. These plasma cell proliferations frequently result in scattered osteolytic bone lesions and extensive skeletal destruction. Myeloma bone lesions are frequently located in the spine, and are associated with debilitating bone pain and an increased rate of pathologic fractures and mortality. The aim of this study was to investigate the incidence of vertebral compression fractures (VCFs) and spinal instability in patients with MM. Patients and methods:Newly diagnosed patients with MM with computed tomography (CT) scans of the spine within three months of diagnosis were identified through an electronic patient database. Clinical baseline data were manually extracted from the patient charts. Fractured levels were graded on CT scans following the Genant grading system, and spinal instability was assessed through the Spinal Instability Neoplastic Score (SINS). Results:A total of 385 patients with 6289 eligible vertebrae were eligible for inclusion. The mean age at diagnosis was 67 years, and 60% were male. At least one VCF was present in 180 patients (47%). A quarter of fractures were classified as severe. The incidence of fractures increased with more advanced disease stages, and men were more likely to have a fracture than women. Conclusions:Our data show that 47% of MM patients present with one or more VCFs at the onset of their disease, of which 20% were classified as unstable, meaning a surgical consultation is recommended.

Background & aims: The European Societies for Clinical Nutrition and Metabolism (ESPEN) and Blood and Marrow Transplantation (EBMT) recommend enteral nutrition (EN) as the first-choice medical nutrition therapy in acute myeloid leukemia (AML) patients undergoing intensive treatments, including high-dose remission-induction chemotherapy and hematopoietic stem cell transplantation (HSCT). However, parenteral nutrition (PN) remains the preferred method of nutrition support in current clinical practice. The aim of this qualitative study was to gain insight into hematologists' experiences and perspectives regarding the choice and ESPEN/EBMT recommendations on EN versus PN. Methods: Online semi-structured interviews were conducted with one hematologist from each of the 21 hospitals offering intensive AML treatments in the Netherlands, using Microsoft Teams. Interviews were audio-recorded, transcribed verbatim and thematically analyzed using Atlas. ti. One hundred nineteen hematologists working in the same hospitals were invited to complete a short online questionnaire survey (SurveyMonkey & REG;) regarding their knowledge and opinion on the ESPEN/EBMT guidelines rec-ommending EN over PN during intensive AML treatments. The results of this survey are presented in a descriptive way. Results: Fifty-nine hematologists participated in this study (42% overall response rate), of which 21 in the semi-structured interviews (response rate 100%) and 38 in the online survey (response rate 32%). He-matologists considered medical nutrition therapy important for prevention and treatment of malnutri-tion and associated adverse outcomes in AML patients undergoing intensive remission-induction treatment and HSCT. However, opposed to the ESPEN/EBMT guidelines, the vast majority of hematolo-gists were hesitant or reluctant to use EN instead of PN as the first-choice medical nutrition therapy in these patients. The most frequently cited barriers to use EN were the expected low feasibility and tolerance of EN, feeding tube-related discomfort and bleeding risk, and patient refusal. Other barriers to follow the guidelines on EN were related to personal factors, including hematologists' knowledge (lack of awareness and familiarity) and attitude (lack of agreement, outcome expectancy, experience, success, motivation, and learning culture), guideline-related factors (lack of evidence and applicability), and external factors (lack of collaboration and resources). Facilitators included strategies for nutrition edu-cation and dissemination of nutritional guidelines, interprofessional and patient collaboration, avail-ability of feeding tubes that can be inserted without endoscopy and stronger scientific evidence.

Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission rates as more intensive chemotherapy regimens in literature. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed MYC-R DLBCL patients in the Netherlands. Eligible patients from the observational cohort that were not included in the interventional trial served as control group in the present risk-adjusted comparison. R2CHOP treated patients from the interventional trial (n = 77) were younger than patients in the R-CHOP control cohort (n = 56) (median age 63 versus 70 years, p = 0.018) and they were more likely to have a lower WHO performance score (p = 0.013). We adjusted for differences at baseline using 1:1 matching, multivariable analysis, and weighting using the propensity score to reduce treatment-selection bias. These analyses consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.51, and 0.59, respectively, for OS, and 0.53, 0.59, and 0.60 for PFS. Thus, this non-randomized risk-adjusted comparison supports R2CHOP as an additional treatment option for MYC-R DLBCL patients.

BACKGROUND Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking. METHODS In a phase 3, open-label trial, we randomly assigned, in a 1:1:1:1 ratio, fit patients with CLL who did not have TP53 aberrations to receive six cycles of chemoimmunotherapy (fludarabine-cyclophosphamide-rituximab or bendamustine-rituximab) or 12 cycles of venetoclax-rituximab, venetoclax-obinutuzumab, or venetoclax-obinutuzumab-ibrutinib. Ibrutinib was discontinued after two consecutive measurements of undetectable minimal residual disease or could be extended. The primary end points were undetectable minimal residual disease (sensitivity, <10-4 [i.e., <1 CLL cell in 10,000 leukocytes]) as assessed by flow cytometry in peripheral blood at month 15 and progression-free survival. RESULTS A total of 926 patients were assigned to one of the four treatment regimens (229 to chemoimmunotherapy, 237 to venetoclax-rituximab, 229 to venetoclax-obinutuzumab, and 231 to venetoclax-obinutuzumab-ibrutinib). At month 15, the percentage of patients with undetectable minimal residual disease was significantly higher in the venetoclax-obinutuzumab group (86.5%; 97.5% confidence interval [CI], 80.6 to 91.1) and the venetoclax-obinutuzumab-ibrutinib group (92.2%; 97.5% CI, 87.3 to 95.7) than in the chemoimmunotherapy group (52.0%; 97.5% CI, 44.4 to 59.5; P<0.001 for both comparisons), but it was not significantly higher in the venetoclax-rituximab group (57.0%; 97.5% CI, 49.5 to 64.2; P = 0.32). Three-year progression-free survival was 90.5% in the venetoclax-obinutuzumab-ibrutinib group and 75.5% in the chemoimmunotherapy group (hazard ratio for disease progression or death, 0.32; 97.5% CI, 0.19 to 0.54; P<0.001). Progression-free survival at 3 years was also higher with venetoclax-obinutuzumab (87.7%; hazard ratio for disease progression or death, 0.42; 97.5% CI, 0.26 to 0.68; P<0.001), but not with venetoclax-rituximab (80.8%; hazard ratio, 0.79; 97.5% CI, 0.53 to 1.18; P = 0.18). Grade 3 and grade 4 infections were more common with chemoimmunotherapy (18.5%) and venetoclax-obinutuzumab-ibrutinib (21.2%) than with venetoclax-rituximab (10.5%) or venetoclax-obinutuzumab (13.2%). CONCLUSIONS Venetoclax-obinutuzumab with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL. (Funded by AbbVie and others; GAIA-CLL13 ClinicalTrials.gov number, NCT02950051; EudraCT number, 2015-004936-36.).

Chronic lymphocytic leukemia (CLL)-related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients' HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and >= 2 impairments present in 60% of patients predicted grade >= 3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043.

Background: Patients with diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements (DLBCL/HGBL- MYC/BCL2, hereafter HGBL- MYC/BCL2) respond poorly to standard immunochemotherapy treatment compared with DLBCL not otherwise specified (LBCL-NOS) patients without a MYC rearrangement. This suggests a negative interaction between MYC and the immune system. As novel T-cell and NK-cell based immunotherapeutic approaches emerge as potential treatment options for aggressive lymphomas, we conducted comprehensive immune profiling to compare peripheral blood T-cells and NK-cells of HGBL- MYC/BCL2 with LBCL NOS patients. Methods: Peripheral blood mononuclear cells (PBMCs) were prospectively collected from HGBL- MYC/BCL2 patients (registered in the HOVON-152 trial, NCT03620578), LBCL-NOS (registered in the HOVON-902 cohort, NCT04139252) and age-matched healthy donors (HDs). Flow-cytometry-based immune profiling of T-cells and NK-cells was performed on baseline samples available from n=66 HGBL- MYC/BCL2 patients (median age 62 years), n=67 LBCL NOS patients (median age 69 years) and n=17 HDs (median age 64 years). The flow cytometry data were computationally analyzed using FlowSOM and UMAP. T-cells were also functionally assessed for intracellular cytokine secretion (ICS) after stimulation with PMA/ionomycin (4h) and proliferation after stimulation with CD3/CD28 beads (5 days) using CellTrace Violet. NK-cells were assessed for cytotoxicity against K562 and degranulation (CD107a/b upregulation) after 4h. Mann-Whitney's U tests were used to compare HGBL-MYC/BCL2 patients with LBCL-NOS patients (primary comparison), and for pairwise comparisons of the lymphoma groups with HDs. To correct for baseline characteristics (age), linear regression analysis was performed. Results: CD4 + helper T-cells did not significantly between the lymphoma subgroups, but were decreased in LBCL-NOS patients as compared to HDs. Frequencies of cytotoxic CD8 + and CD4 +CD8 + T-cells did not significantly between the lymphoma subgroups and were similar as in HDs. Regulatory T-cell (Treg) frequencies of HGBL- MYC/BCL2 patients were similar to that of HDs, but were decreased in LBCL NOS patients. The frequency of CD4 -CD8 - T-cells was increased in LBCL NOS patients. Previously activated (HLA-DR +) CD4 + and CD8 + T-cells, as well as recently activated CD25 +, CD38 + or CD127 + CD4 + T-cells (Figure 1A) or activated/exhausted (PD-1 +) CD4 + T-cells and PD1 + Tregs were increased in both lymphoma subtypes (Figure 1B), but only HGBL- MYC/BCL2 displayed an increase in PD1 + CD8 + T-cells (Figure 1B). Conversely, recently activated CD8 + T-cells were decreased exclusively in LBCL NOS. HGBL- MYC/BCL2 patients and HDs had similar percentages of T-cells with a senescent phenotype (CD28 -CD57 +KLRG1 +), but the frequency of T-cells with this senescent phenotype was increased in LBCL NOS patients (Figure 1A), also after adjustment for age. Despite all these phenotypic differences, functional in vitro assays detected no differences in proliferation or cytokine secretion of peripheral T-cells from HGBL- MYC/BCL2 patients, LBCL NOS patients and HDs. In the NK-cell compartment, both lymphoma subtypes contained lower frequencies of CD56 brightTim3 +, CD56 bright/dimDNAM-1 + NK-cells, but LBCL NOS patients expressed a higher amount of NK-cells expressing inhibitory receptor NKG2A compared with HDs. NK-cells of HGBL- MYC/BCL2 patients, LBCL NOS patients and HDs displayed similar cytotoxic activity, suggesting no apparent functional impairment. Conclusions: HGBL- MYC/BCL2 patients have a distinct peripheral T-cell and NK-cell phenotype from LBCL NOS patients without a MYC rearrangement, but show no apparent functional deficiencies in terms of proliferation, cytokine secretion or cytotoxic activity. These results are not contradicting the application of T-cell and NK-cell based immunotherapeutic approaches for patients with aggressive B-cell lymphoma. Simultaneously, it emphasize the need to investigate the potential immunomodulatory impact of lymphoma intrinsic MYC in the tumor microenvironment.

Background Thrombopoietin receptor agonists are frequently used in treating immune thrombocytopenia (ITP) owing to high response rates and good tolerability. ITP is associated with an increased risk of thrombosis. Whether treatment with eltrombopag further increases this risk is controversial. The mechanisms behind the thrombotic risk in ITP are unclear. Objectives To assess platelet function and hypercoagulability in patients with ITP and the effect of eltrombopag thereon. Methods This prospective multicenter study assessed adult primary patients with ITP who were starting eltrombopag treatment. Platelet (re)activity and hypercoagulability were measured in whole blood or plasma before start and after 2 to 3 weeks of eltrombopag treatment and compared with those of controls. Change over time was assessed by mixed-effects models, and the results were corrected for multiple testing. Results We included 16 patients and 33 controls. At baseline, patients with ITP exhibited lower expression of glycoprotein VI, more activated platelets, and lower reactivity toward agonists compared with controls. β-Thromboglobulin levels reduced and thrombin generation peak height increased compared with those of controls. In line with this finding, patients with ITP showed high factor VIII (median, 217%; IQR, 174%-272%) and von Willebrand factor levels (median, 167%; IQR, 109%-198%). Eltrombopag treatment increased thrombin generation potential: lag time decreased and peak height and endogeneous thrombin potential increased. The latter changes were not significant after correction for multiple testing. Conclusion Patients with ITP in this study were in a hypercoagulable state, with preactivated platelets, increased thrombin generation potential, and increased levels of factor VIII and von Willebrand factor. Eltrombopag treatment further increased plasma thrombin generation potential but no other hemostatic parameters.

Figure 1: Doxorubicin dose-response plot. Dose-response curve for continuous doxorubicin dose and breast cancer risk, adjusted for age at HL treatment, chest radiotherapy and gonadotoxic treatment. Adjusted HRs for doxorubicin dose categories are added. Background: Female Hodgkin lymphoma (HL) survivors treated with chest radiotherapy at a young age have a strongly increased risk of breast cancer (BC). Recent studies in childhood cancer survivors have shown that doxorubicin may also increase BC risk. So far, the association between doxorubicin and BC risk has not been examined in cancer survivors treated at adolescent/adult ages. Methods: We assessed BC risk in a cohort of 1964 female five year HL survivors, treated at ages 15–50 years in 20 Dutch hospitals between 1975 and 2008. Cumulative BC incidence was estimated in the presence of death as a competing risk. Treatment factors were time-dependently included in the multivariable Cox regression analysis, focusing on the effect of doxorubicin exposure on BC risk. Results: HL survivors were treated at a median age of 27.8 years (interquartile range (IQR) 21.9–35.2 years). After a median follow-up of 18.3 years (IQR 12.9–24.7) years, 200 women had developed invasive BC (n=190) and/or ductal carcinoma in situ (n=49). The 30-year cumulative incidence was 19.4% (95% confidence Interval (CI) 16.6–22.3%). Among patients treated with chemotherapy (n=1113), receipt of doxorubicin-containing chemotherapy increased from 32.6% in 1975–1986 to 84.5% in 1998–2008. In multivariable analysis a cumulative dose of >200 mg/m2 was associated with increased BC risk (HR 1.7; 95% CI 1.1–2.4), compared to patients not treated with doxorubicin. BC risk increased 19% (HR 1.19; 95% CI 1.1–1.3) per additional 100 mg/m2 doxorubicine (ptrend=0.003). Receipt of mantle or axillary field irradiation or gonadotoxic therapy did not modify the association between doxorubicin and BC risk. Among patients who received >200 mg/m2 doxorubicin, the HR was 1.6 (95% CI 1.1–2.5) for patients treated with and 2.0 (95% CI 0.9–4.2) for patients treated without mantle or axillary field irradiation (Pinteraction=0.35). Gonadotoxic treatment (>8.4 g/m2 procarbazine or pelvic irradiation) significantly decreased the risk of BC. Conclusion: This study shows that doxorubicin is associated with an increased BC risk among adolescent and adult HL survivors. Now that radiotherapy doses and volumes have decreased and doxorubicin increasingly forms the backbone of HL treatment, the potential association of doxorubicin with increased BC risk is an important issue.