Lymphomas comprise a complex and heterogeneous group of malignancies which pose challenges in understanding their epidemiology, pathobiology, treatment responses and long-term outcomes. Evolving diagnostic classification and fast-paced therapy development compound these challenges. Robust real-world data (RWD) collection and analysis using clinical registries can contribute significantly to address gaps in understanding of practice variation and provide evidence for health technology assessments. However, to maximize the impact of lymphoma registries, and those in other diseases, there is a compelling need for global collaboration, data harmonization and automated integration between registries and other large datasets. Technologies that enable safer data sharing are already available, but historical legal frameworks and evolving privacy concerns are not keeping pace, undermining their intended purpose and limiting the full potential of available high-quality RWD to improve patient care. This White Paper written by the Global Lymphoma Registry Alliance (LyRA) discusses the importance and value of lymphoma registries for different stakeholders as well as benefits of forming a global alliance of the registry network. An alliance such as LyRA serves both academic endeavors and public interest through collaboration between patient and community organizations, policy-makers, regulatory authorities, industry and others seeking to use RWD. Bringing these stakeholders together and raising awareness more broadly will facilitate timely clinical trial result contextualization and innovation in public-private collaborations on novel trial emulations and designs, including external comparator cohorts. The LyRA leadership propose strategies for overcoming barriers to facilitate these key collaborations towards improving patient outcomes on a global scale.

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.

Introduction Detection of measurable residual disease (MRD) at end-of-treatment (EOT) using ultrasensitive circulating tumor DNA (ctDNA) assays is predictive of relapse risk (Roschewski et al., ASH 2024; Wang et al., ASCO 2025). Prior studies have shown that ctDNA-based molecular response assessment early during therapy also holds promise for risk stratification (Kurtz et al., JCO; Nat Biotechnol). These advances have enabled ctDNA-guided treatment escalation and de-escalation strategies in ongoing prospective DLBCL trials (Nijland et al., ICML 2025; Cherng et al., ASCO 2025). However, comprehensive real-world data capturing the full longitudinal dynamics of ctDNA in large B-cell lymphomas (LBCLs) are lacking. Methods We analyzed ctDNA in patients enrolled in HOVON-902, a prospective, multicenter, real-world study of blood-based response monitoring in LBCL patients receiving R-CHOP or DA-EPOCH-R induction therapy. Plasma samples were collected at up to 11 time points: baseline (C1D1), at interim induction cycles (C2D1, C3D1, C4D1), at EOT (defined as end of induction), and during surveillance (every 3 months in year 1 and every 6 months in year 2). Patient-specific phased variants (PVs) were identified using PhasED-Seq from FFPE or baseline plasma with matched germline DNA (Foresight CLARITY, Boulder, CO). PVs were tracked longitudinally to detect MRD at key treatment milestones and to assess previously defined molecular response kinetics (early molecular response [EMR], major molecular response [MMR]) in relation to best observed response (BOR) according to Lugano 2014 response criteria, PFS and OS. Results We monitored ctDNA MRD in >1000 serial plasma samples from >150 patients with LBCLs (94% DLBCL-NOS, 6% HGBCL), using PVs successfully identified from either FFPE or baseline plasma. The median age was 68 years (19-88), 66% were male, 80% had advanced-stage disease (Lugano III/IV), and 20% had Low, 30% Low Intermediate, 28% High Intermediate, and 22% High IPI risk. At a median follow-up of 37 months (1.4-55.4), the 3-year PFS and OS were 81% and 88%, respectively. Overall, more patients cleared MRD with each successive cycle during 1L therapy. Specifically, MRD detection decreased over time during induction, with preliminary on-treatment MRD clearance rates of 28%, 51%, 64%, and 81% at C2D1, C3D1, C4D1, and EOT, respectively. MRD status was prognostic at each landmark (P<0.05 for all), but with increasing prognostic value over time. Consistent with the therapeutic effect of additional treatment cycles, outcomes for MRD+ patients at each landmark worsened throughout therapy. For example, initial results show a 3-yr PFS of MRD+ patients after 1 cycle of 69% (at C2D1), as compared to 11% at EOT. Outcomes were also correlated with early ctDNA response kinetics: when considering quantitative response thresholds, EMR (2-log10 decrease in [ctDNA]) and MMR (2.5-log10 decrease) were both significantly associated with 3-year PFS. For example, preliminary results show lack of EMR associated with significantly inferior 3-year PFS (EMR, HR 3.2, 95% CI 1.7-5.9, p < 0.001). We also considered the role of disease surveillance after the end of induction therapy. With the addition of surveillance samples, initial results show that 91% of patients with confirmed DLBCL relapse were MRD+ at either the EOT or during follow-up, representing a 17% increase in clinical sensitivity for detecting relapse. Conversely, among patients who did not relapse, 96% had negative EOT MRD, and 99% had either negative EOT MRD or achieved MRD clearance during follow-up. Interesting and distinctive temporal and kinetic patterns of MRD detection as a function of anatomic site of relapse, relapse histology, and response to consolidative or secondary therapies will be presented, along with corresponding lead times relative to current surveillance practice strategies and estimates of potentially avoidable radiographic studies. Conclusions This is the first real-world study of ctDNA dynamics across serial time points in a uniformly treated LBCL cohort. Our findings confirm the prognostic value of on-treatment MRD and molecular response assessment. Post-EOT ctDNA monitoring reflects the temporal relationship between tumor burden detection and relapse, highlighting its potential for early detection. Our study provides a comprehensive overview of ultrasensitive MRD detection and how it might inform personalized surveillance and treatment strategies for LBCL.

ABSTRACT Comprehensive insights are lacking into why patients with hematological malignancies (HMs) receive no cancer‐directed treatment. We evaluated socio‐demographic and cancer‐related characteristics, decision‐making rationales, and overall survival in patients with three common HMs―diffuse large B‐cell lymphoma (DLBCL), symptomatic multiple myeloma (MM), and acute myeloid leukemia (AML)―who do not receive cancer‐directed treatment, using the nationwide Netherlands Cancer Registry. A total of 26 945 patients diagnosed with DLBCL (47%), symptomatic MM (29%), or AML (25%) between 2014 and 2021 were included. About 16% of the patients did not receive cancer‐directed treatment, ranging from 26% in AML to 15% in DLBCL and 10% in MM. The primary reason for not receiving cancer‐directed treatment in all three HMs was related to physical condition. The second main reason was patient/family choice in DLBCL and MM, whereas in AML it was rapid disease progression. In female patients, patient/family choice was a more prevalent reason for not receiving cancer‐directed treatment than in male patients. Patients with a lower socio‐economic position more often did not receive cancer‐directed treatment. Median OS varied by reason for not receiving cancer‐directed treatment, with the shortest OS in patients experiencing rapid disease progression or death before treatment initiation (0·4 to 0·6 months).

Burkitt lymphoma is a rare lymphoma entity that represents less than 5% of adult lymphomas. Although prognosis has improved with dose-dense therapy, Burkitt lymphoma remains an area of clinical and biological research with specificities due to the high incidence of CNS involvement and tumour lysis syndrome in patients with a high tumour burden. Few consensus recommendations are available concerning diagnosis, treatment, and prognostic factors in adult patients. In this Review, a European Reference Network on Rare Haematological Diseases (ERN-EuroBloodNet) expert panel has reviewed recent advances in the management of Burkitt lymphoma in the first-line setting to develop updated evidence-based and expert opinion-based recommendations on the management of this disease. The expert panel consisted of ten clinicians and pathologists involved in the clinical management of Burkitt lymphoma from eight EU member states. Additionally, two haematologists were included to support the systematic review process. A balanced representation was ensured between individuals affiliated and not affiliated with ERN-EuroBloodNet. Together with providing current indications on diagnosis and risk-adapted first-line therapy, the Review contains specific recommendations for the identification and management of important complications of Burkitt lymphoma such as tumour lysis syndrome and CNS-oriented therapy, and recommendations for prognostic assessment to guide treatment. Finally, unresolved questions for Burkitt lymphoma are highlighted, including questions around genetics, imaging, and second-line therapies, along with patient perspective.

Introduction: Large B-cell lymphomas (LBCL) exhibit intra-patient biologic heterogeneity. Single-site biopsies limit comprehensive assessment of this complexity, which circulating tumor DNA (ctDNA) overcomes by detecting mutations from distinct anatomical sites. We have previously shown anatomical genomic heterogeneity can be quantified by integrating baseline ctDNA and tissue profiles (Goldstein, ASH 2024). Though aberrant somatic hypermutation (aSHM) drives lymphomagenesis, its contribution to anatomical heterogeneity, clonal evolution, and outcomes is poorly understood. We validate the clinical value of anatomical genomic heterogeneity in diverse aggressive lymphomas, delineate its relation to aSHM, and then propose a DLBCL clonal evolution model. Methods: We studied 588 specimens from 196 patients across 3 cohorts with comprehensive genotyping of baseline plasma and matched tumor tissues. The Discovery Cohort included 66 LBCL patients from a multinational cohort receiving front-line chemoimmunotherapy with pre-treatment tumor, germline and plasma genotyping by CAPP-Seq (Kurtz, JCO 2018). We developed the Metric Of Spatial Anatomic Intra-tumoral genomic Complexity (MOSAIC) as the root mean square error of a linear regression model of mutant allele frequencies (log[VAF]) in ctDNA versus those shared in tissue. After defining a MOSAIC threshold in our Discovery Cohort, two validation cohorts with pre-treatment tumor, germline and plasma samples and treated with front-line chemoimmunotherapy were used: 97 LBCL patients from the HOVON-902 study profiled by PhasED-seq (Wang, ASCO 2025) and 33 MCL patients from the LyMa trial profiled by CAPP-Seq (Tessoulin, 18-ICML). To elucidate clonal evolution, we explored the molecular associations and relationship of aberrant somatic hypermutation (aSHM) with anatomic heterogeneity and outcomes in LBCL. We defined aSHM rate as the fraction of ctDNA mutations occurring within canonical aSHM targets (Schmitz, NEJM 2017). We measured clonal architecture (sciclone) and molecular subtypes (LymphGen) and performed survival analysis (Kaplan-Meier; Cox models). Results: In our Discovery Cohort, 100% had SNVs unique to plasma, with median 15% of plasma mutations absent in paired tissue. The median MOSAIC was 0.235 (threshold for validation) with range 0.1-0.4. Cases with >1 subclone in plasma had higher MOSAIC (median 0.26 vs 0.19,p=0.002). MOSAIC did not correlate with age, COO, histological subtype, Stage, or IPI. However, high MOSAIC was associated with worse PFS (HR=4.3,p=0.01) and OS (HR=12.7,p=0.02). MOSAIC did not correlate with ctDNA burden and remained prognostic independent of ctDNA levels. In the MCL LyMa Validation Cohort, median MOSAIC was 0.28 (IQR 0.13-0.39). MOSAIC correlated with ctDNA burden (p=0.05) and LDH (p=0.01), but not with leukemic status, blastoid morphology, or Ki67. High MOSAIC predicted worse PFS (HR 13.6,p=0.01), independent of LDH and ctDNA level. In the LBCL HOVON-902 Validation Cohort, median MOSAIC was 0.21 (IQR 0.17-0.28) with 38% classified as high. BN2, EZB & A53 tumors by LymphGen had higher MOSAIC (median 0.26), while MCD had lower scores (median 0.18). High MOSAIC was again associated with inferior PFS (HR=2.3,p=0.04) and OS (HR=3.4,p=0.02) and higher end of treatment MRD+ rates (28% vs 12%). TP53 and P2RY8 mutations were associated with high MOSAIC patients. GCB tumors showed numerically higher aSHM rates, though no significant differences in aSHM rates by histology or stage were found. Lower aSHM rate correlated with higher MOSAIC (r= -0.4,p=0.001) and worse PFS (HR 4.4,p=0.02). Patients with both high MOSAIC and low aSHM rate (38%) had 5-year PFS 43% (HR 5.6,p=0.001) and OS 57% (HR 9.8,p=0.003), vs 87 and 93% respectively. In 80%of patients, median plasma VAF for aSHM exceeded non-aSHM mutations, indicating aSHM occurs early in lymphomagenesis. High MOSAIC patients had higher ratios of median aSHM to non-aSHM VAFs, consistent with ongoing subclonal evolution via non-aSHM mutations. Conclusions: We describe and validate a novel biomarker measuring anatomical genomic heterogeneity, integrating plasma and tissue profiles, that independently predicts prognosis for front-line chemoimmunotherapy. We show that aSHM aberrations occur early in clonal evolution and likely initiate lymphomagenesis. Low aSHM rates and high anatomical heterogeneity in B-cell lymphomas define a high-risk subgroup prone to treatment resistance via anatomical clonal divergence.

Complement-dependent cytotoxicity (CDC) is an important effector function of various therapeutic antibodies. Cancer resistance to CDC is primarily attributed to extracellular factors. Using diffuse large B-cell lymphoma (DLBCL) models, we elucidated intracellular evasion mechanisms. By CRISPR-Cas9 library screening, we identified mitochondrial damage and reactive oxygen species as the key intracellular drivers of CDC. CDC resistance was linked to augmented mitochondrial mass, elongated mitochondria and reduced mitophagy, and decreased expression of actin-related genes. Actin downregulation in CDC-resistant cells occurred specifically within the mitochondria, connecting mitochondrial rearrangements and cytoskeletal dynamics with resistance. Stimulating actin polymerization could partially overcome CDC resistance. Of clinical significance, we observed a positive association between the cytoskeleton and antibody responses in DLBCL patient samples. In conclusion, our study unveils novel intracellular resistance mechanisms to antibody-induced CDC, highlighting the critical roles of mitochondrial rearrangements and cytoskeletal dynamics in CDC. We propose that decreased mitochondrial actin prevents overload of the mitophagy pathway, thereby reducing CDC.

Dexrazoxane has been studied for its ability to prevent anthracycline-induced cardiac dysfunction (AICD) in several trials but its use in clinical practice remains limited. This is related to the low to moderate quality of the generated evidence, safety concerns and restricted prescribing indications. Additional randomized trials are needed before this drug can be routinely integrated into cardio-oncology clinical practice. To describe the rationale and design of the HOVON 170 DLBCL – ANTICIPATE trial. This trial aims to establish the efficacy and safety of dexrazoxane for the primary prevention of AICD in patients diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) treated with six cycles R-CHOP21 chemo-immunotherapy. This is a multicenter, parallel-group, open-label, phase III trial, randomizing 324 patients between either no cardioprotective treatment or dexrazoxane from the first R-CHOP cycle. The primary and co-primary endpoints are the incidence of AICD within 12 months of registration and the percentage of patients with complete metabolic remission at the end-of-treatment PET-CT respectively. The trial is registered at the EU Clinical Trials Register (EU-CT number 2023-505377-32) and ClinicalTrials.gov (NCT06220032). The medical research ethics committee approved the trial in May 2024. Recruitment has started in September 2024 and is expected to last for three years. This trial is poised to contribute crucial evidence concerning the efficacy and safety on the use of dexrazoxane in the primary prevention of AICD. The trial is anticipated to address critical knowledge gaps and offer important insights into the value of dexrazoxane in cardio-oncology practice.

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.

MYC oncogene rearrangements ( MYC -R) negatively affect survival in patients with Ann Arbor stage III–IV diffuse large B-cell lymphoma (DLBCL), but their impact in limited stage (LS) I–II is unclear. Therefore, we assessed the impact of MYC -R on progression-free survival (PFS) and overall survival (OS) in LS DLBCL patients at the population level. We identified 1,434 LS DLBCL patients with known MYC -R status diagnosed between 2014 and 2020, who received R-CHOP(-like) regimens using the Netherlands Cancer Registry, with survival follow-up until February 2022. Stage I patients with ( n = 83, 11%) and without ( n = 650, 89%) a MYC -R had similar 2-years PFS (89% and 93%, p = 0.63) and OS (both 95%, p = 0.22). Conversely, stage II DLBCL patients with a MYC -R ( n = 90, 13%) had inferior survival outcomes compared to stage II patients without a MYC -R ( n = 611, 87%) (PFS 70% vs. 89%, p = 0.001; OS 79% vs. 94%, p < 0.0001). Both single MYC -R (single hit, n = 36) and concurrent BCL2 and/or BCL6 rearrangements (double/triple hit, n = 39) were associated with increased mortality and relapse risk. In conclusion, in stage II DLBCL a MYC -R is negatively associated with survival. In stage I DLBCL, however, survival outcomes are excellent irrespective of MYC -R status. This challenges the diagnostic assessment of MYC -R in stage I DLBCL patients.

The aim of this study was to validate a previously developed deep learning model in 5 independent clinical trials. The predictive performance of this model was compared with the international prognostic index (IPI) and 2 models incorporating radiomic PET/CT features (clinical PET and PET models). Methods: In total, 1,132 diffuse large B-cell lymphoma patients were included: 296 for training and 836 for external validation. The primary outcome was 2-y time to progression. The deep learning model was trained on maximum-intensity projections from PET/CT scans. The clinical PET model included metabolic tumor volume, maximum distance from the bulkiest lesion to another lesion, SUVpeak, age, and performance status. The PET model included metabolic tumor volume, maximum distance from the bulkiest lesion to another lesion, and SUVpeak. Model performance was assessed using the area under the curve (AUC) and Kaplan-Meier curves. Results: The IPI yielded an AUC of 0.60 on all external data. The deep learning model yielded a significantly higher AUC of 0.66 (P < 0.01). For each individual clinical trial, the model was consistently better than IPI. Radiomic model AUCs remained higher for all clinical trials. The deep learning and clinical PET models showed equivalent performance (AUC, 0.69; P> 0.05). The PET model yielded the highest AUC of all models (AUC, 0.71; P < 0.05). Conclusion: The deep learning model predicted outcome in all trials with a higher performance than IPI and better survival curve separation. This model can predict treatment outcome in diffuse large B-cell lymphoma without tumor delineation but at the cost of a lower prognostic performance than with radiomics.

Given the rarity of primary central nervous system lymphoma (PCNSL), evaluations of different high-dose methotrexate-(HD-MTX)-based treatment regimens is sparse. This retrospective, multicenter study evaluates clinical characteristics and outcomes (progression-free, overall and disease-specific survival) after five HD-MTX-based polychemotherapeutic regimens and two consolidation therapies. 346 patients with histologically confirmed PCNSL, treated with ≥ 1 cycle HD-MTX-based strategies (≥3g/m2/cycle) were included. The regimens included MATRIX (HD-MTX, HD-AraC, thiotepa, and rituximab), (R)MBVP±HD-AraC (HD-MTX, teniposide/etoposide, carmustine, prednisolone, ± HD-AraC, ± rituximab), (R)MP (HD-MTX, procarbazine, ± rituximab), and a combination of HD-MTX and HD-AraC. The overall response rate after induction was 69 %, 28 % complete remission and progressive disease was observed in 100 (29 %) patients. 126 (36 %) patients received consolidation, including high-dose-BCNU-thiotepa with autologous stem cell transplantation (HD-BCNU-TT/ASCT, n = 59 (17 %)) or whole brain radiotherapy (WBRT, n = 67 (19 %)). Clinical characteristics associated with adverse mortality risk by multivariable prognostication contained age > 60 years (HR 1.61, p = 0.011), elevated LDH (HR 1.75, p = 0.004) and WHO status ≥ 2 (HR 1.56, p = 0.010). Independently, induction regimens containing HD-AraC demonstrated survival benefit compared to induction regimens without HD-AraC (HR 0.59, p = 0.002). Without preference for HD-BCNU-TT/ASCT or WBRT, a favorable effect of consolidation (HR 0.44 and HR 0.42, p < 0.001) was confirmed, also with consolidation as time-dependent variable. Competing risk analysis showed similar low incidence of lymphoma-unrelated deaths in consolidated and unconsolidated patients. This study confirms that age, elevated LDH and WHO status increase the mortality risk. HD-AraC containing treatment regimens and consolidation with HD-BCU-TT/ASCT or WBRT were associated with superior survival, including a favorable low incidence of lymphoma-unrelated deaths.

Introduction. Post-transplant lymphoproliferative disorder (PTLD) comprises a spectrum of hematological malignancies that develop after solid organ transplantation (SOT). Unlike diffuse large B-cell lymphoma (DLBCL), initial treatment of PTLD patients starts with rituximab monotherapy. Identifying patients who do not respond to rituximab is essential to prevent delay in administering chemotherapy. We previously showed that cell-free tumor DNA (ctDNA) isolated from plasma represents a promising approach to profile PTLD at diagnosis [PID 37705050]. The use of ctDNA as biomarker has shown feasible in DLBCL, but has not yet been established for PTLD. We aimed to explore the feasibility of ctDNA for genomic profiling and response assessment in PTLD. Methods. Plasma samples of 28 PTLD patients were collected in this prospective observational multi-center cohort study in the Netherlands (National trial registry 7402). Low-coverage whole genome sequencing (lcWGS) was performed for detection of copy number variants (CNVs). Ultra deep (median ~15.000x target coverage) targeted next generation sequencing (NGS) was performed for the detection of single nucleotide variants (SNVs). The targeted panel contained 117 genes (comprising 391 kb) known to be recurrently mutated in B-cell lymphomas. SNVs were called using an in-house pipeline, optimized for detecting small somatic variants with low variant allele frequencies (VAFs) [PID 37705050]. For baseline samples, the VAF cutoff was set to >0.5%. For follow-up timepoints, this cutoff was removed to further increase sensitivity. ctDNA concentrations based on the VAF of SNVs were expressed as haploid genomic equivalent per milliliter (hGE/mL) of plasma. IchorCNA was used to call CNVs. Results. Median age of patients was 57 years (range 29-74), with 68% presenting with Ann Arbor stage III - IV. Median time between SOT and PTLD was 68 months (range 3-379). SOT consisted of kidney (n=17, 61%), liver (n=7, 25%), lung (n=3, 11%) and hematopoietic stem cell transplant (n=1, 4%). Pathology review showed DLBCL (19/24), Burkitt like (1/24), polymorphic PTLD (1/24) and undetermined B-cell lymphomas (3/24). EBV was negative for 10 (45%), positive for 12 (55%) and unknown for 2 cases. Out of 28 patients, 21 (75%) started initial treatment with rituximab, 6 (21%) initiated R-CHOP therapy and one patient (4%) did not receive treatment. In total 92 plasma samples were analyzed. At diagnosis, a total of 285 SNVs were detected in cfDNA samples of 27 out of 28 (96%) patients. The median number of SNVs per sample was 5 (range 0-35). KMT2C was the most frequently mutated gene (12/28, 43%), followed by ARID1B (8/28, 29%), P2RY8 (7/28, 25%), KMT2D, IGLL5 and TP53 (5/28, 18%). CNVs were detected in 12 out of 21 baseline samples (57%). The most frequent CNVs were gains of 11q and 18q. Out of the 28 PTLD patients, 26 exhibited sufficient baseline mutations to facilitate response assessment, while six cases lacked sufficient number of mutations to reliably calculate and track the hGE/ml. Recurring SNVs were detected in the remaining 20 patients (71%). Of these 20 cases, 16 patients initiated treatment with rituximab monotherapy, whereas 4 patients started directly with R-CHOP. Within the subset receiving rituximab monotherapy, 7 patients continued with rituximab alone, while 9 patients escalated to R-CHOP. Among the 7 patients who continued rituximab monotherapy, a rapid decline in ctDNA levels was observed in 6 patients as early as four weeks post-treatment initiation. Of the 9 patients who escalated to R-CHOP, plasma samples from interim timepoints revealed that 7 patients tested positive for minimal residual disease (MRD), while 2 patients tested negative. For the 4 patients who initiated treatment with R-CHOP, follow-up assessments revealed that 2 tested positive for MRD, while the remaining 2 tested negative. Overall, we were able to detect MRD with a sensitivity of as low as 0.2% VAF or 1 hGE/mL of plasma in follow-up timepoints. Clinical outcomes were available for most patients (n=17), while this is pending for the other patients (n=11). Conclusion. Our study demonstrates that ctDNA analyses are highly suitable for detecting CNVs and SNVs in diagnostic and follow-up plasma samples from PTLD patients. This approach can be used to molecularly profile PTLD and track disease activity over time. Correlation of ctDNA dynamics with FDG-PET scan results and clinical outcome is ongoing.