Christian Brieghel’s research while affiliated with Copenhagen University Hospital and other places

The revised international staging system (R-ISS) in multiple myeloma (MM) was recently updated as the second R-ISS (R2-ISS) and refined prognostication in clinical trial populations. By including 2929 Danish patients with MM and complete data on R2-ISS registered from 2005 through 2019, we validated the R2-ISS for overall survival (OS) in a population-based cohort; however, only partly among younger patients. We thus developed a real-world international staging system (RW-ISS) from a 75% training cohort. Feature selection and weighted scores of high-risk variables from a Cox regression model of OS included age >70 years (2 points), performance status (PS) > 1 (2 points), PS 1 (1 point), t(14;16) (1 point), ISS III (1 point), ISS II (0.5 points), high lactate dehydrogenase (0.5 points), and del(17p) (0.5 points). In the test set, patients with RW-ISS I (0–2.0 points, 38.2%), II (2.5–3.0 points, 19.8%), III (3.5–4.5 points, 27.1%), and IV (5.0–7.0 points, 15.0%) demonstrated a median OS of 9.5, 5.5, 3.4, and 1.1 years, respectively (P < 0.0001) and the C-index was superior for RW-ISS as compared to both R2-ISS and R-ISS (0.708 vs 0.604 vs 0.595, respectively). RW-ISS was in part externally validated. We thus recommend using RW-ISS in routine clinical care of NDMM.

Background Lymphoid-lineage cancers (LC; International Classification of Diseases, 10th edition [ICD10] C81.x-C90.x, C91.1-C91.9, C95.1, C95.7, C95.9, D47.2, D47.9B, and E85.8A) share many epidemiological and clinical features, which favor meta-learning when developing medical artificial intelligence (mAI). However, access to large, shared datasets is largely missing and limits mAI research. Aim Creating a large-scale data repository for patients with LC to develop data-driven hematology. Methods We gathered electronic health data and created open-source processing pipelines to create a comprehensive data resource for Danish LC Research (DALY-CARE) approved for epidemiological, molecular, and data-driven research. Results We included all Danish adults registered with LC diagnoses since 2002 (n=65,774) and combined 10 nationwide registers, electronic health records (EHR), and laboratory data on a high-powered cloud-computer to develop a secure research environment. Among other, data include treatments (ie 21,750 cytoreductive treatment plans, 21.3M outpatient prescriptions, and 12.7M in-hospital administrations), biochemical analyses (77.3M), comorbidity (14.8M ICD10 codes), pathology codes (4.5M), treatment procedures (8.3M), surgical procedures (1.0M), radiological examinations (3.3M), vital signs (18.3M values), and survival data. We herein describe the data infrastructure and exemplify how DALY-CARE has been used for molecular studies, real-world evidence to evaluate the efficacy of care, and mAI deployed directly into EHR systems. Conclusion The DALY-CARE data resource allows for the development of near real-time decision-support tools and extrapolation of clinical trial results to clinical practice, thereby improving care for patients with LC while facilitating streamlining of health data infrastructure across cohorts and medical specialties.

In chronic lymphocytic leukemia, the reliability of next‐generation sequencing (NGS) to detect TP53 variants ≤10% allelic frequency (low‐VAF) is debated. We tested the ability to detect 23 such variants in 41 different laboratories using their NGS method of choice. The sensitivity was 85.6%, 94.5%, and 94.8% at 1%, 2%, and 3% VAF cut‐off, respectively. While only one false positive (FP) result was reported at >2% VAF, it was more challenging to distinguish true variants <2% VAF from background noise (37 FPs reported by 9 laboratories). The impact of low‐VAF variants on time‐to‐second‐treatment (TTST) and overall survival (OS) was investigated in a series of 1092 patients. Among patients not treated with targeted agents, patients with low‐VAF TP53 variants had shorter TTST and OS versus wt‐TP53 patients, and the relative risk of second‐line treatment or death increased continuously with increasing VAF. Targeted therapy in ≥2 line diminished the difference in OS between patients with low‐VAF TP53 variants and wt‐TP53 patients, while patients with high‐VAF TP53 variants had inferior OS compared to wild type‐TP53 cases. Altogether, NGS‐based approaches are technically capable of detecting low‐VAF variants. No strict threshold can be suggested from a technical standpoint, laboratories reporting TP53 mutations should participate in a standardized validation set‐up. Finally, whereas low‐VAF variants affected outcomes in patients receiving chemoimmunotherapy, their impact on those treated with novel therapies remains undetermined. Our results pave the way for the harmonized and accurate TP53 assessment, which is indispensable for elucidating the role of TP53 mutations in targeted treatment.

Secondary CNS involvement (SCNSL) is a rare manifestation of diffuse large B-cell lymphoma (DLBCL) with a poor prognosis. We present updated data from a nationwide study on the incidence and clinical characteristics of SCNSL. The incidence of SCNSL was calculated considering death or relapse without SCNSL as competing risks. Risk factors associated with SCNSL were identified using a cause-specific Cox proportional hazards model. A total of 1972 patients with DLBCL were included and 68 (3.4%) of these experienced SCNSL at first relapse. The crude 1- and 2-year cumulative incidence of SCNSL was 2.0% (95% CI, 1.5-2.7) and 2.6% (95% CI, 2.0-3.4). For patients with a high-risk CNS International Prognostic Index (CNS-IPI) score, the 1- and 2-year cumulative incidence was 6.4% and 7.5%. The number and location of extranodal (EN) sites was the most significant predictor of SCNSL. Specific EN sites associated with increased risk were bone marrow, heart, kidneys/adrenal glands, ovaries, testes and uterus. Median overall survival (OS) after SCNSL was 3.2 months. SCNSL within six months after end of primary treatment (EOT) was associated with a higher baseline CNS-IPI score and worse OS compared to SCNSL more than six months after EOT. Patients with a combination of low-risk CNS-IPI and late-onset SCNSL had the most favorable prognosis. In conclusion, updated real-world population-based data on SCNSL at first relapse, adjusted for competing risks, demonstrated a lower incidence of SCNSL than previously reported, with the number and location of EN sites being the most significant predictors of SCNSL.

Introduction: Frontline fludarabine and cyclophosphamide plus rituximab (FCR) has until recently been considered the standard of care for fit younger patients (<65 years [y]) with chronic lymphocytic leukemia (CLL), who are immunoglobulin heavy chain variable gene (IGHV) mutated. Established 25 years ago, the IGHV germline identity (ID) of <98% vs ≥98% has defined IGHV mutational status mutated (M) vs unmutated (U), respectively (Hamblin et al., and Damle et al., Blood 1999). FCR leads to long-term progression-free survival (PFS) for patients with IGHV-M (median PFS 14.6 y; Thompson et al, Blood 2024) also described as a potential functional cure, although the risk of secondary malignancy and therapy-related myeloid neoplasms is significant (da Cunha-Bang et al., BJH 2021). In recent years, targeted treatments have largely replaced chemoimmunotherapy (CIT). Thus, it is debated whether FCR is still a relevant treatment option possibly providing a clinical cure for a subset of patients. Here, we investigated whether patients with deeply mutated (D) IGHV may indeed benefit from FCR. Methods: We retrospectively included patients diagnosed with CLL between Jan 2008 and Apr 2021 in the Danish CLL register, who were up to 65 years of age when they received frontline FCR. Information on IGHV germline identity (ID) was collected nationwide from three central laboratories. Patients were grouped according to IGHV germline ID: IGHV-U (≥98%) vs IGHV intermediately mutated (IGHV-I; 94-98%) vs IGHV-D (<94%). With real world data missing consistent information on CLL progression, we analyzed treatment-free survival (TFS) as time to next treatment or death (composite event) using the Kaplan-Meier method and followed patients until next treatment, death, or end of follow-up. The log-rank test was used to compare 10-y overall survival (OS) and TFS. Results: In total, 269 patients received frontline FCR including 255 (94.8%) with information on IGHV status, while information on IGHV germline ID was available for 178 patients (66.2%): 120 (67.4%) 36 (20.2%), and 22 (12.4%) patients were IGHV-U, IGHV-I, and IGHV-D, respectively. At time of diagnosis, the 269 patients had a median age of 55 years (interquartile range [IQR] 50-60), the median age was similar between patients with IGHV-D, IGHV-I and IGHV-U (56 [IQR 48-61] vs 55 [IQR 50-59] vs 56 [IQR 50-60], respectively), 67.7% were male, 45.0% were Binet stage A at diagnosis, 60.2% were IGHV-U, and 5.6% had a 17p deletion, which was exclusively seen among IGHV-U patients. OS upon FCR was numerically longer in patients with IGHV-M compared to IGHV-U (10-y OS 74.6% vs 67.9%, respectively; P=0.13). As expected, patients with IGHV-M demonstrated longer TFS as compared to those with IGHV-U (10-y TFS 64.0% vs 33.6%, respectively; p=0.00019). Subdividing the IGHV-M group into IGHV-I and IGHV-D, patients who were IGHV-D demonstrated longer OS (10-y OS 100% vs 79.7% vs 67.2%, respectively) and longer TFS (10-y TFS 100% vs 73.5% vs 28.8%, respectively) compared to both IGHV-I and IGHV-U. A significant difference was found between IGHV-D and IGHV-I regarding both OS (P=0.030) and TFS (P=0.022) using the pairwise log-rank test. Conclusion: In this population-based real-world study, younger CLL patients treated with frontline FCR demonstrated excellent long-term OS and TFS in a smaller subset of patients (12%) with deeply mutated IGHV (IGHV-D) with germline ID below 94%. Upon external validation, IGHV-D - rather than IGHV status alone - could identify patients with a high likelihood of being cured with FCR. By contrast, less than 3 of 4 patients with intermediately mutated IGHV (94-98% germline ID) remained alive and without second line treatment after 10 years follow-up; these patients should thus be offered targeted therapies.

Background Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic precursor to multiple myeloma (MM) and some lymphoproliferative disorders. Effective risk stratification is important to guide work-up and follow-up of individuals with MGUS. A key part of the current risk stratification is serum free light chain (FLC) levels and ratio, included as part the Mayo Clinic risk stratification model. However, existing refence intervals have been shown to be inaccurate, partly due to the effect of age and renal function. This has led to the development of revised reference intervals, based on FLC measures from 75,422 individuals in the Iceland screen, treats, or prevents multiple myeloma (iStopMM) study (Long, 2023). The revised intervals improve light-chain MGUS diagnostics, but the implications for MGUS with monoclonal (M) proteins is unknown. Methods We used the nationwide Danish Lymphoproliferative Cancer Research Center (DALY-CARE) data resource on patients with lymphoid cancers between 2008 to 2023 (Brieghel, 2024). We extracted ICD10 coded MGUS diagnoses and included individuals with relevant laboratory data available, including FLC measurements (from laboratories using the Freelite assay), creatinine, and a detectable M protein. Date of MGUS diagnosis was set at the first detection of an M protein with adjacent FLC measurement. We excluded patients with a concomitant diagnosis of MM, lymphoma, or AL amyloidosis prior to or <90 days after of MGUS diagnosis. First, individuals were stratified into 1) abnormal FLC ratio according to revised reference intervals, 2) abnormal FLC ratio according to old reference intervals only, and 3) normal FLC ratio by both old and the revised reference intervals. In the revised intervals, the FLC ratio is only considered abnormal with a concurrent abnormal absolute FLC level. Second, we stratified individuals into the Mayo Clinic MGUS risk groups using the old and revised reference intervals, respectively. In both analyses, outcome was defined as progression to either a) MM or b) MM, lymphoma, or AL amyloidosis. We used cause-specific Cox regression with censoring upon death, end of follow-up, or progression to lymphoproliferative disease not included in the outcome. Results A total of 6,401 individuals with MGUS met the inclusion criteria. These had a median age of 72 years (IQR: 64-79), 47% were female, and the median follow-up time was 4.1 years (2.0-6.4). During follow-up, 248 (3.9%) progressed to MM, 77 (1.2%) to lymphoma, and 19 (0.3%) to AL amyloidosis. At MGUS diagnosis, the FLC ratio was abnormal in 2,556 (40%) and 1,223 (19%) individuals according to old and revised intervals, respectively. The FLC ratio of 1,333 (21%) individuals reclassified from abnormal to normal, when changing from the old to revised reference interval. When comparing these to the individuals with normal FLC ratio), we found no difference in the risk of progression to MM (HR 1.04, 95%CI: 0.73-1.49) or to MM, lymphoma, or AL amyloidosis combined (HR 1.17, 95%CI: 0.87-1.58). By contrast, the 1,223 (19%) individuals with abnormal FLC ratio according to the revised reference intervals had an increased risk of progression to MM (HR 2.81, 95%CI: 2.14-3.70) and the grouped diagnoses (HR 2.64, 95%CI: 2.08-3.35). Using the revised reference intervals, the number of cases classified as low-risk MGUS increased from 2488 to 3194 (1.3-fold increase). Still, the 5-year cumulative incidence of MM progression for low-risk MGUS was similar when using the old and revised reference intervals (3.7% and 3.6%, respectively). The 765 individuals who were reclassified to low-risk from a higher risk group did not have a higher MM progression risk compared to individuals who classified as low-risk using both reference intervals (HR 0.91, 95% CI: 0.56-1.49). Conclusion This population-based study identified fewer MGUS individuals with abnormal FLC and FLC ratio with the revised iStopMM reference intervals compared to the old. Importantly, for the cases where FLC ratio was reclassified from abnormal to normal, the risk of progression did not differ from those with normal FLC ratios. Using the revised reference intervals, more MGUS individuals were categorized as low-risk without altering the risk of MM progression. The findings validate the revised reference interval for FLC and demonstrate that they can improve the prognostic value of FLC testing and optimize care to individuals with MGUS.

Introduction: Improving health-related quality of life (HRQoL) is a critical treatment objective for patients with chronic lymphocytic leukemia (CLL) due to its incurable nature. The HOVON 141/Vision trial has demonstrated high efficacy for MRD-guided, time-limited treatment with ibrutinib plus venetoclax (IV) in patients with relapsed or refractory (RR) CLL. However, data on the impact of MRD-guided IV on HRQoL remain limited. Methods: Assessment of HRQoL in patients with RR CLL was conducted within the framework of the HOVON 141/Vision study as a pre-planned analysis. RR CLL patients were treated with IV for 15 cycles. In patients with detectable MRD (≥10-4), I was continued, while patients with undetectable MRD (uMRD in blood and bone marrow, < 10-4) were randomized 1:2 for I maintenance or treatment cessation. Upon MRD recurrence in the treatment cessation arm, IV was reinitiated followed by I maintenance (Niemann 2024). Changes in functioning scales, global health status (GHS)/QoL, and symptoms were assessed using the EORTC QLQ-C30 and QLQ-CLL16 questionnaires, completed at baseline, the end of IV (cycle 15), and at 6 months, 1, 2, and 3 years after cycle 15. Minimal important differences (MID) were used to determine whether changes in scores are clinically meaningful. MIDs were calculated using a distribution-based approach (van der Straten, Blood 2023). Results: 224 patients completed at least one questionnaire and were included in the analysis. At baseline, the mean GHS of the full cohort was 66. After 15 cycles of IV, the majority of patients reported clinically relevant improvement (positive change in score >8, the MID) or stable GHS (change between +8 and -8) (44% and 41% respectively), while 15% showed a clinically relevant decrease in GHS (negative change in score >8, the MID). A clinically relevant improvement in the mean GHS was observed after 15 cycles of IV (+10; 95% CI +7 to +13). Similarly, a clinically relevant decrease in future health concerns was observed (-12; 95% CI -8 to -16). After induction treatment, 72 patients with uMRD were randomly assigned to a treatment group, 24 to ibrutinib maintenance (uMRD I) and 48 to treatment cessation (uMRD cessation). The remaining patients continued with ibrutinib monotherapy (I continuation). One year after the end of induction (EOIT) treatment, the majority of patients reported a clinically relevant improvement or stable GHS: 24% and 57% for uMRD I, 22% and 65% for uMRD cessation, and 21% and 64% for I continuation. In the full cohort, 6 months after induction treatment, a clinically relevant improvement was seen in the GHS (+11; 95% CI 8 to 14), fatigue (-12; 95% -9 to -15), disease-related symptoms (-12; 95% CI -10 to -14), and future health worries (-17; 95% CI -13 to -21) compared to baseline. These effects persisted up until 3 years after the EOIT. A transient increase in treatment-related symptoms and diarrhea was observed at the EOIT (+8; 95% CI 5 to 11 and +14; 95% CI 10 to 18 respectively). However, these symptom scores returned to the baseline scores 6 months after the EOIT in each treatment group. Clinically relevant improvements were observed 1 year after the end of IV compared to baseline for GHS (+9), role functioning (+16), emotional functioning (+9), cognitive functioning (+7), and future health worries (-17) in the uMRD I arm. In the uMRD cessation arm, improvements were observed for GHS (+11), fatigue (-14), disease-related symptoms (-12), and future health worries (-15). In the I continuation arm improvements were observed for GHS (+12), physical functioning (+6), role functioning (+11), fatigue (-15), dyspnea (-15), disease-related symptoms (-14), and future health worries (-17). Conclusion: MRD-guided treatment with IV significantly improves HRQoL for RR CLL and mitigates fatigue, disease-related symptoms, and health concerns. These effects are durable, lasting for at least three years after end of induction treatment with IV. The clinically relevant improvements in GHS and health concerns are seen in patients continuing ibrutinib, as well as after cessation. Overall, MRD-guided IV therapy confers substantial HRQoL benefits in RR CLL, in addition to the previously documented high efficacy of IV MRD-guided time-defined treatment.

Background: Patients with chronic lymphocytic leukemia (CLL) exhibit considerable risk of severe infections already prior to needing treatment. Despite this, clinical tools identifying patients-at-risk are an unmet need along with management strategies for high-risk CLL patients who do not fulfill iwCLL treatment criteria. PreVent-ACaLL (NCT03868722) is a phase 2 clinical trial applying the machine learning-based CLL treatment infection model (CLL-TIM) to identify newly diagnosed CLL patients with high risk of severe infections and/or early treatment (Agius et al., Nat Comm, 2020). High-risk patients are randomized between 3 cycles of preemptive acalabrutinib+venetoclax (A+V) or watch and wait (WW). We recently demonstrated that CLL patients needing treatment exhibited innate immune dysfunction characterized by excessive granulocyte activation and monocyte “exhaustion” with skewed cytokine response to toll-like receptor (TLR) stimulation. Immune function was restored upon treatment with BTK- and BCL2 inhibitors in parallel with a reduced infectious burden (Teglgaard et al., CCR, 2024). We here investigate innate immune dysfunction changes upon preemptive A+V or WW in context of the PreVent-ACaLL phase 2 trial. Methods: Fifteen patients included thus far in PreVent-ACaLL were randomized 1:1 between preemptive A+V or WW. Blood samples were assessed at baseline, after 12 weeks (end of treatment), and after 24 weeks. Innate immune function was assessed in fresh whole-blood samples by TruCulture, a clinically implemented functional assay quantifying cytokine release in response to standardized immune stimuli (lipopolysaccharide [LPS] for TLR4; single-stranded RNA-virus analogue resiquimod [R848] for TLR7/8) and an unstimulated control. Concurrently, extensive immunophenotyping of immune cell subsets in fresh whole blood was assessed by an 8-tube, 10 color flow cytometry panel (DuraClone). Baseline data were compared to previous data from 35 CLL patients needing treatment (outside the trial). All patients provided written informed consent, and the study was approved by the Ethics Committee and the Data Protections Agency. Results: At baseline, LPS- and R848 stimulated release of IFN-γ and IL-10 was reduced and R848-stimulated release of IL-8 and TNF-α was elevated in CLL patients included in PreVent-ACaLL (n=15) compared to normal reference levels, with cytokine levels comparable to CLL patients needing treatment. Unstimulated IL-8 and TNF-α were also elevated in PreVent-ACaLL patients, similar to- or exceeding the levels observed for CLL patients needing treatment. In the treatment arm (n=8), R848-stimulated IL-10 release normalized during the 24 weeks (p=0.02). R848 stimulated- and unstimulated IL-8 and TNF-α normalized upon A+V while remaining elevated in patients from the WW arm (n=7) (A+V vs WW at 24 weeks: p=0.02 [R848-IL8], 0.04 [R848-TNFα], and 0.04 [Unstim-IL-8]). Notably, normalization of unstimulated cytokines first occurred at 24 weeks (12 weeks post treatment). Immunophenotyping data will be included for the presentation. Conclusion: Functional immune assessment of the first fifteen patients enrolled in the phase 2 PreVent-ACaLL trial for newly diagnosed patients with CLL at high risk of infection and/or treatment indicates increased inflammatory activity along with dysregulated innate immune responses similar to patients with progressive CLL needing treatment. Despite a small sample size, we observed signs of innate immune restoration and reduced inflammation in patients receiving preemptive A+V for 12 weeks as compared to the WW arm. These findings are coherent with our previous observations of innate immune restoration upon treatment with acalabrutinib monotherapy or ibrutinib+venetoclax in CLL patients needing treatment (Teglgaard et al., CCR, 2024). Thus, we here for the first time provide early data indicating that preemptive treatment may improve immune function and thus reduce infectious risk in high-risk newly diagnosed CLL, further emphasizing the role of data-driven decision support tools for CLL infectious risk assessment and management. The PreVent-ACaLL trial is ongoing, awaiting clinical results within the coming years.

Introduction The HOVON141/VISION trial (NCT03226301) randomized patients with relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), who achieved undetectable minimal residual disease (uMRD; <10-4) after 15 cycles (C15) of ibrutinib plus venetoclax (I+V), to either continued ibrutinib (arm A) or treatment cessation (arm B); patients with detectable MRD (dMRD; ≥10-4) at C15 could not be randomized and continued ibrutinib (non-randomized). Patients, who converted to dMRD during treatment cessation (arm B), re-initiated I+V. Previously reporting a 12-month progression-free survival (PFS) of 98% after treatment cessation, time-limited and MRD guided I+V is feasible and attractive in RR CLL (Kater 2022). So far, however, classic CLL biomarkers have failed to predict outcomes on I+V. In this study, we investigated whether CLL gene mutations may predict clinical outcomes on MRD-guided I+V. Methods Baseline samples underwent capture-based sequencing using the Genomic Medicine Sweden Lymphoid Gene Panel (GMS-LGP); covering 252 genes and applying unique duals indices and unique molecular identifiers. Single-nucleotide variants and small indels in 25 known CLL driver genes (Brieghel et al, Clin Cancer Res 2020) were called down to 1% variant allele frequency using BALSAMIC pipeline (SciLifeLab), and variants were manually curated in VarSeq 2.5.0 (Golden Helix) excluding variants with a frequency > 1% in GnomAD and those classified as benign and likely benign according to the ACMG. Results For this study, baseline samples were available in 176 of 225 included patients: 19/24 (79%) in arm A, 36/48 (75%) in arm B and 121/153 (79%) non-randomized patients; including 89/116 (77%) with dMRD at C15 continuing ibrutinib. We identified a total of 397 mutations (mean 2.3 mutation per patient) most commonly identified in SF3B1 (27%), TP53 (20%), ATM (20%), NOTCH1 (19%), BIRC3 (17%), BCOR (9%), NFKBIE (7%), XPO1 (7%), MGA (7%), DDX3X (6%), MED12 (6%), BRAF (6%), FBXW7 (6%), POT1 (5%), and ZMYM3 (5%). IGHV status was unmutated in 113 of 163 (69.3%) patients. No particular mutated gene was significantly enriched in patients with IGHV unmutated status (pairwise Fisher's exact tests; p = 0.076 for NOTCH1, but otherwise p > 0.32). Harboring NRAS and XPO1 mutations correlated with high MRD levels at C15 (p = 0.025 and p = 0.0050, respectively), whereas the number of mutated drivers and mutated pathways did not. No associations between mutations in specific genes and PFS were observed in arms A and B (uMRD) or in non-randomized patients (dMRD). In arm B (uMRD; treatment cessation), no specific gene mutation was associated with re-initiating I+V during treatment cessation. Of note, the I+V re-initiation rate was 100% for patients with TP53 mutations. For the entire cohort, BCOR (hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.2-7.0), CCND2 (HR 5.9, 95% CI 1.4-25.0), and XPO1 (HR 3.2, 95% CI 1.2-8.3) mutations were associated with shorter overall survival (OS). NRAS (HR 7.7 95% CI 1.0-58.2) and XPO1 (HR 5.7 95% CI 2.2-14.6) mutations were associated with shorter PFS. A combined BCOR, CCND2, NRAS and XPO1 (BCNX) mutation-status correlated with significantly higher MRD levels at C15 (p = 0.011), significantly shorter PFS (HR 4.1, 95% CI 2.2-7.8; p < 0.0001) and OS (HR 4.1, 95% CI 2.0-8.4; p < 0.0001) as compared to patients without BCNX mutations (median OS 60.8 months vs not reached [NR] and median PFS 51.7 months vs NR, respectively). Thus, impairment of different signaling pathways engaging the BCNX genes (i.e. NF-κB, DNA damage, MAPK-ERK, and RNA processing, respectively) seems to impact outcome upon I+V treatment for RR CLL. Conclusion BCNX (BCOR, CCND2, NRAS and XPO1) mutations at baseline predict poor MRD response, PFS, and OS on MRD guided I+V in RR CLL. An updated analysis on all 252 sequenced lymphoma-associated genes will be presented at the meeting.