BACKGROUND:Indolent systemic mastocytosis (ISM), a clonal mast cell disease primarily driven by the KIT D816V mutation, can cause long-term debilitating symptoms and poor quality of life. Most patients rely on symptom-directed best supportive care (BSC) medications, which do not treat the underlying driver of ISM. Avapritinib, an oral, potent, selective KIT D816V inhibitor, is approved in adults with ISM. OBJECTIVE:We sought to understand the long-term efficacy and safety of avapritinib in ISM. METHODS:The PIONEER trial (NCT03731260) enrolled adults with moderate to severe ISM symptoms. Patients initiated avapritinib 25 mg once daily (QD; recommended dose) plus BSC in part 1, 2, or 3; open-label part 3 is ongoing with up to 5 years of follow-up. As per investigator discretion and disease burden, a dose increase up to avapritinib 50 mg QD was permitted in part 3. RESULTS:As of February 21, 2025, 226 patients initiated avapritinib at 25 mg QD. The median (range) treatment duration was 40.0 (0.7-67.2) months. Patients receiving avapritinib experienced durable and clinically meaningful symptom improvement (mean change, -19.39 [n = 127] in the Indolent Systemic Mastocytosis Symptom Assessment Form total symptom score) through approximately 3 years. Avapritinib continued to be well tolerated for a longer term with a safety profile comparable with the previously reported placebo-controlled portion. Most treatment-related adverse events (TRAEs) were grades 1 to 2, with limited grade 3 or higher reported. Edema events were the most frequent TRAEs (mostly grade 1). Serious TRAEs occurred in 3 patients (1%), and 7 patients (3%) discontinued treatment because of TRAEs. CONCLUSIONS:Long-term follow-up (median, ∼3 years) demonstrates that avapritinib is effective and well tolerated. Avapritinib shows a favorable benefit-risk profile as a chronic ISM treatment.

Abstract Advanced systemic mastocytosis (AdvSM), comprising aggressive systemic mastocytosis, mast cell leukemia, and systemic mastocytosis with an associated hematological neoplasm, is a heterogeneous myeloid neoplasm with poor prognosis. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative treatment, yet its benefit across AdvSM subtypes in the era of KIT-targeted tyrosine kinase inhibitors (TKIs) such as midostaurin and avapritinib remains unclear. To identify patient subgroups benefiting from allo-HCT and to define prognostic factors for post-transplant survival, we analyzed 631 AdvSM patients from the European Competence Network on Mastocytosis registry, including 69 who underwent allo-HCT. Treatment effects were assessed using time-dependent Cox regression in a transplant-eligible complete-case cohort ( n = 419). In this cohort, allo-HCT showed no overall survival (OS) benefit (hazard ratio [HR] 1.21, 95% CI 0.80–1.84; p = 0.37), whereas TKI response emerged as a strong independent predictor of survival (HR 0.42; p <0.001). Subtype-stratified analysis revealed an allo-HCT benefit exclusively in patients with systemic mastocytosis associated with acute myeloid leukemia ( n = 30; HR 0.20; p = 0.020). Among the 69 transplanted patients, median OS was 49.6 months with 2-year and 5-year survival of 63% and 46%, respectively. The International Prognostic Scoring System for Mastocytosis (IPSM) at transplantation independently predicted both OS (HR per category 1.68; p = 0.026) and progression-free survival (HR 1.99; p = 0.003), whereas the Mutation-Adjusted Risk Score and diagnostic subtype did not reach statistical significance. Competing risk analysis demonstrated that higher IPSM captured both relapse-related and transplant-related mortality. These findings suggest that the survival benefit of allo-HCT in AdvSM is driven primarily by control of the associated myeloid neoplasm. Accordingly, allo-HCT should be prioritized in patients with SM-AML, whereas TKI-directed strategies may be preferred in other subtypes, with IPSM at transplantation potentially guiding transplant selection and timing.

The tick-borne bacterium Neoehrlichia (N.) mikurensis causes latent infections that can become symptomatic when B-cell defenses are compromised. We investigated the prevalence of N. mikurensis in two cohorts of Swedish patients: a prospective cohort (n = 186) evaluated for lymphoma and a retrospective cohort (n = 198) diagnosed with seven lymphomas. Samples were tested for N. mikurensis by PCR. Nine of 116 patients (7.8%) diagnosed with lymphoma in the prospective cohort, and 7/198 (3.5%) in the retrospective cohort had a concomitant N. mikurensis infection. Indolent lymphomas, particularly marginal zone lymphoma (9.3%), were frequently coupled with N. mikurensis infection. Males had higher risk of having lymphoma and N. mikurensis infection. N. mikurensis was diagnosed in 3.2% of patients without lymphoma, making it the most common infectious differential diagnosis for possible lymphoma. This emerging pathogen should therefore be considered as a differential diagnosis for patients with suspected lymphoma in N. mikurensis-endemic regions.

Systemic mastocytosis (SM) is a spectrum of hematologic disorders characterized by accumulation of atypical mast cells (MCs) in extracutaneous organs. SM with an associated hematologic neoplasm (SM-AHN), the most frequent subtype of advanced SM, is predominantly associated with myeloid neoplasms, consistent with shared clonal architecture. Because of its rarity and heterogeneity, robust outcome data aligned with contemporary classifications are needed to inform risk stratification. We analyzed the 10th data wave of the European Competence Network on Mastocytosis registry (34 European centers and 1 US center). SM and AHN diagnoses followed the 2022 World Health Organization classification. Baseline characteristics and overall survival (OS) were compared between patients with myeloid SM-AHN and SM without AHN (SM-no-AHN). Within SM-AHN, outcomes were analyzed by SM component (advanced: aggressive SM [ASM] or MC leukemia [MCL] vs. non-advanced: bone marrow mastocytosis, indolent SM, or smoldering SM) and AHN subtype. Among 3,925 patients with SM, 467 (11.9

Introduction: Treatment options for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) remain limited. While several fixed-duration combination therapies have been introduced in the frontline setting as alternatives to continuous treatment, approved fixed-duration options in the R/R setting are currently limited to the BCL2 inhibitor venetoclax combined with the anti-CD20 antibody rituximab (VR). Although VR has demonstrated efficacy in R/R CLL, many patients do not experience deep remissions with undetectable minimal residual disease (uMRD), and most patients eventually relapse. Obinutuzumab, a type II anti-CD20 antibody, has shown greater efficacy than rituximab as first-line CLL treatment, but randomized data are currently lacking for R/R CLL. Sonrotoclax (BGB-11417), a next-generation BCL2 inhibitor, is a more selective and more pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. In an ongoing phase 1/1b study (NCT04277637; BGB-11417-101), sonrotoclax monotherapy has demonstrated preliminary antitumor activity in patients with R/R CLL, and sonrotoclax combination treatments are currently being evaluated in separate study cohorts. The CLL-RR1/CELESTIAL-RRCLL study is designed to evaluate whether sonrotoclax in combination with anti-CD20 antibodies can provide superior clinical outcomes compared with the current venetoclax-based standard treatment in patients with R/R CLL or SLL. An exploratory analysis will evaluate the efficacy of MRD-guided vs. fixed-duration therapy in this population. Methods: CLL-RR1/CELESTIAL-RRCLL (NCT06943872) is an ongoing phase 3, randomized, open-label, multicenter study conducted in collaboration between BeOne Medicines Ltd and the German CLL Study Group. Approximately 630 adults with active R/R CLL or SLL who have received ≥1 prior treatment will be randomized 2:2:1:2 to sonrotoclax plus obinutuzumab (SO), sonrotoclax plus rituximab (SR), SO with MRD-guided therapy (SO-MRD), or venetoclax plus rituximab (VR). Randomization will be stratified by del(17p)/TP53 mutation status, prior BCL2 inhibitor treatment, and refractoriness to prior BTK inhibitor treatment (ie, prior progression on BTK inhibitor therapy). Patients must meet iwCLL 2018 treatment criteria and have received ≥1 prior therapy for CLL/SLL; those with prior BCL2 inhibitor treatment are eligible if they achieved a remission lasting ≥3 years and have been off treatment for ≥2 years, consistent with ESMO CLL treatment recommendations. A minimum of 80% of the study population must have received prior therapy with a targeted agent. Patients with Richter transformation are excluded from the study. SO, SR, or VR will be administered for 25 cycles, each cycle lasting 28 days. Patients in the SO-MRD arm will receive 14 cycles of treatment and will either stop treatment if MRD is confirmed to be undetectable (<10−4) in peripheral blood or will complete a total of 25 cycles if MRD ≥10−4. On day 1 of cycle 1, oral sonrotoclax (SO, SR, SO-MRD arms) will be initiated using a ramp-up to the target dose (320 mg) or oral venetoclax (VR arm) will be initiated with a ramp-up to the target dose (400 mg). Rituximab (SR, VR arms) will be administered intravenously at 375 mg/m2 on day 1 of cycle 2 and at 500 mg/m2 on day 1 of cycles 3 to 7. Obinutuzumab (SO, SO-MRD arms) will be administered intravenously at 1,000 mg on days 1/2, 8, and 15 of cycle 2 and on day 1 of cycles 3 to 7. The primary endpoint of the trial is progression-free survival (PFS) of SO vs VR, determined by a blinded independent review committee. The key secondary (powered) endpoint is the PFS of SR vs VR; additional secondary endpoints include uMRD rates at cycle 14, complete response rates, overall survival, and safety/tolerability. The SO-MRD arm is considered exploratory and is designed to evaluate the efficacy and feasibility of shortening MRD-guided treatment in the context of achieving deeper remissions with SO. Further exploratory analyses will evaluate baseline molecular and cytogenetic features, MRD dynamics, and potential predictors of response or resistance. The study is enrolling at approximately 150 sites across North America, Europe, Asia-Pacific, including Australia/New Zealand and China/Korea, and Latin America. Recruitment began in June 2025 and is currently ongoing.

Despite the well-established adverse impact of del(11q) in chronic lymphocytic leukemia (CLL), the prognostic significance of somatic ATM mutations remains uncertain. We evaluated the effects of ATM aberrations (del(11q) and/or ATM mutations) on time-to-first-treatment (TTFT) in 3631 untreated patients with CLL, in the context of IGHV gene mutational status and mutations in nine CLL-related genes. ATM mutations were present in 246 cases (6.8%), frequently co-occurring with del(11q) (112/246 cases, 45.5%). ATM-mutated patients displayed a different spectrum of genetic abnormalities when comparing IGHV-mutated (M-CLL) and unmutated (U-CLL) cases: M-CLL was enriched for SF3B1 and NFKBIE mutations, whereas U-CLL showed mutual exclusivity with trisomy 12 and TP53 mutations. Isolated ATM mutations were rare, affecting 1.2% of Binet A patients and <1% of M-CLL cases. While univariable analysis revealed shorter TTFT for Binet A patients with any ATM aberration compared to ATM-wildtype, multivariable analysis identified only del(11q), trisomy 12, SF3B1, and EGR2 mutations as independent prognosticators of shorter TTFT among Binet A patients and within M-CLL and U-CLL subgroups. These findings highlight del(11q), and not ATM mutations, as a key biomarker of increased risk of early progression and need for therapy, particularly in otherwise indolent M-CLL, providing insights into risk-stratification and therapeutic decision-making.

ABSTRACT:Patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) are treated with fixed-duration B-cell lymphoma 2 inhibitors + CD20 monoclonal antibodies or continuous Bruton tyrosine kinase (BTK) inhibitors. Although continuous treatment may lead to cumulative toxicity or resistance, fixed-duration treatment may lead to undertreatment and early relapse. Efficacy and safety of minimal residual disease (MRD)-guided treatment cessation of ibrutinib + venetoclax (I+V) with reinitiated I+V upon MRD conversion was evaluated in the randomized VISION/HO41 phase 2 study. Four-year follow-up including long-term toxicity and MRD kinetics are reported. Patients received ibrutinib for 2 (28-day) cycles followed by 13 cycles of I+V. Patients reaching undetectable MRD at 4 years (<10-4, flow cytometry) in the blood and bone marrow at cycle 15 (C15) were randomized 2:1 between treatment cessation with reinitiated I+V upon detectable MRD2 (dMRD2; sensitivity of ≥10-2 by flow cytometry) and ibrutinib maintenance. MRD4-positive patients at C15 remained on ibrutinib (dMRD4 arm, defined by MRD sensitivity of ≥10-4 by flow cytometry). With a median of 51.7 months, the estimated 4-year overall survival (OS) was 88%, progression free survival (PFS) was 81%; 14% of patients required next-line treatment (NT). For patients randomized to treatment cessation, 40% had reinitiated therapy per protocol because of dMRD2. No difference between treatment cessation, ibrutinib maintenance, or the dMRD4 arm continuing ibrutinib was seen for OS, PFS, or NT in landmark analysis from C15 time of randomization. Lower toxicity was demonstrated for the treatment-cessation arm. MRD-guided cessation and reinitiation of I+V for R/R CLL is feasible, reduces toxicity compared with indefinite BTK inhibitor, while providing comparable PFS rates. This trial was registered at www.clinicaltrials.gov as #NCT03226301.

BACKGROUND:Treatment of chronic lymphocytic leukemia (CLL) currently consists of two main approaches - continuous therapy with Bruton's tyrosine kinase inhibitors and fixed-duration regimens combining venetoclax with either CD20 antibodies or Bruton's tyrosine kinase inhibitors. Comparisons of these two therapeutic approaches are lacking. METHODS:We conducted an investigator-initiated, phase 3, randomized trial involving patients with previously untreated CLL. Patients were randomly assigned to receive continuous ibrutinib or fixed-duration venetoclax-obinutuzumab or venetoclax-ibrutinib. The primary end point was investigator-assessed progression-free survival (noninferiority margin for the hazard ratio, 1.608, corresponding to a noninferiority margin of 8 percentage points at 3 years). Secondary end points included minimal residual disease (MRD), response, overall survival, and safety. RESULTS:A total of 909 patients were assigned to venetoclax-obinutuzumab (303 patients), venetoclax-ibrutinib (305 patients), or ibrutinib (301 patients). The median follow-up was 34.2 months. In this prespecified interim analysis, 3-year progression-free survival was 81.1% in the venetoclax-obinutuzumab group, 79.4% in the venetoclax-ibrutinib group, and 81.0% in the ibrutinib group (hazard ratio for venetoclax-obinutuzumab vs. ibrutinib, 0.87 [98.3% confidence interval {CI}, 0.54 to 1.41]; hazard ratio for venetoclax-ibrutinib vs. ibrutinib, 0.84 [98.0% CI, 0.53 to 1.32]); the results for each comparison met the criterion for noninferiority. After the end of treatment, MRD in peripheral blood was undetectable in 73.3% of the patients in the venetoclax-obinutuzumab group, 47.2% in the venetoclax-ibrutinib group, and 0% in the ibrutinib group. Three-year overall survival was 91.5%, 96.0%, and 95.7%, respectively. The most common adverse events were infections, gastrointestinal disorders, and cytopenias. CONCLUSIONS:In patients with previously untreated CLL, fixed-duration treatment with venetoclax-obinutuzumab or venetoclax-ibrutinib was noninferior to continuous ibrutinib with regard to investigator-assessed progression-free survival. (Funded by the University of Cologne and others; CLL17 ClinicalTrials.gov number, NCT04608318; EudraCT number, 2019-003854-99.).

Expression of CD2, CD25 and/or CD30 in extracutaneous mast cells (MC) is a minor diagnostic criterion for systemic mastocytosis (SM) in the classification of the World Health Organization and International Consensus Classification. So far, it remains unknown whether expression of these antigens on MC is of prognostic significance in SM. We performed a retrospective multi-center study of patients with SM using the data set of the registry of the European Competence Network on Mastocytosis, including 5034 patients with various MC disorders. The percentage of CD2-, CD25+ and/or CD30+ MC was considerably lower in patients with indolent SM compared to patients with advanced SM, including aggressive SM and MC leukemia. Whereas CD25 and CD30 expression in MC could not be associated with prognosis, we found that lack of CD2 expression in MC is associated with a significantly reduced overall survival (OS) in patients with SM (p < 0.0001). Lack of CD2 was also associated with the presence of extramedullary involvement affecting the spleen, liver, and/or lymph nodes (odds ratio 2.63 compared to SM with CD2+ MC). Together, lack of CD2 expression in MC is a prognostic marker and indicator of reduced OS and extramedullary disease expansion in patients with SM.

Introduction Current treatment for chronic lymphocytic leukemia (CLL) follows two seminal paradigms: continuous Bruton tyrosine kinase inhibitor (BTKi) therapy until progression and fixed-duration regimens combining BCL2 inhibitors with a CD20 antibody or BTKi, typically given over one year. These two different approaches were established through comparisons to chemo(immuno)therapy and are yet to be compared directly. Here we present data of a prospective trial comparing continuous ibrutinib (I) monotherapy to fixed-duration venetoclax plus obinutuzumab (VO) and venetoclax plus ibrutinib (VI) for CLL. Methods CLL17 (NCT04608318) is an investigator-initiated, international, randomized phase 3 trial for patients (pts) with previously untreated CLL. Pts were randomized to receive ibrutinib (I), fixed-duration venetoclax plus obinutuzumab (VO) or fixed-duration venetoclax plus ibrutinib (VI). Randomization was stratified by IGHV status, del(17p)/TP53mut and patient fitness, defined by cumulative illness rating scale (CIRS) score >6 and/or creatinine clearance <70 mL/min. Ibrutinib was given continuously until intolerance or progression; VO consisted of 6 cycles (28 days each) of venetoclax plus obinutuzumab, followed by 6 additional cycles of venetoclax monotherapy; VI was initiated with a 3-cycle ibrutinib lead-in, followed by 12 cycles of VI. The study was designed to test non-inferiority of VO vs I and VI vs I. The primary endpoint was investigator-assessed progression-free survival (PFS). A ≤8% reduction in 3-year (yr) PFS was deemed not clinically meaningful (non-inferiority HR margin 1.608). Per protocol, an interim analysis was planned once 65% of required PFS events (138 of 213) were reached. Secondary endpoints included overall response rate (ORR), undetectable minimal residual disease (uMRD), overall survival (OS) and safety. Results In total, 909 pts were randomized to VO (N=303), VI (N=305), and I (N=301). Data cut-off was on April 11th, 2025, median observation time was 34.2 months (range 0-49). Median age was 66 yrs (34-90), 67.8% were male, median CIRS score was 3 (0-18); 33.7% had a creatinine clearance <70 mL/min. Overall, 7.6% had del(17p) and/or TP53 mutation, 56.5% unmutated IGHV and 19.2% complex karyotype (≥3 aberrations); 53.8% and 6.5% had high or very high CLL-IPI, respectively. Three-yr PFS was 81.1% in the VO arm compared to 81.0% in the I arm (HR 0.87, type-I-error adjusted CI [98.3%] 0.54-1.41) and 79.4% in the VI arm (compared to I arm: HR 0.84, type-I-error adjusted CI [98.0%] 0.53-1.32), respectively, with the upper limit of each adjusted CI below the pre-defined non-inferiority margin, providing early evidence of non-inferiority. At final staging (C18D1), the ORR was 84.2% in the VO arm, 88.5% in the VI arm, and 86.0% in the I arm, with a CR rate of 51.5%, 46.2%, and 8.3%, respectively; the uMRD (<10-4) rate in ITT population in peripheral blood was 73.3% (62.0% in bone marrow) in the VO arm, 47.2% (40.0% in bone marrow) in the VI arm and 0% (0% in bone marrow) in the I arm. At 3 yrs, the OS rate was 91.5% in the VO arm, compared to 95.7% in the I arm (HR 1.67, 95% CI 0.86-3.28) and 96.0% in the VI arm (compared to I: HR 0.96, 95%CI 0.45-2.05), respectively. For pts with unmutated IGHV, 3-yr PFS in the VO arm was 75.8% (87.6% for mutated IGHV) compared to 79.7% (83.5%) in the I arm (HR 0.98, 95% CI 0.61-1.59), and 78.9% (80.0%) in the VI arm (compared to I: HR 0.81, 95% CI 0.49-1.32). For pts with del(17p)/TP53mut, 3-yr PFS in the VO arm was 62.0% (82.7% for pts without del(17p)/TP53mut) compared to 79.4% (81.0%) in the I arm (HR 1.20, 95% CI 0.40-3.59), and 69.0% (80.1%) in the VI arm (compared to I: HR 0.70, 95% CI 0.22-2.16). The most frequent AEs were infections and infestations (VO: 76.3%, VI: 80.2%, I: 79.9%), gastrointestinal disorders (VO: 59.7%, VI: 74.3%, I: 63.4%), and blood and lymphatic system disorders (VO: 59.0%, VI: 42.9%, I: 28.5%). Covid-19 infection was reported in 38.3%, 42.2% and 39.3% of pts; cardiac disorders occurred in 13.9%, 23.8% and 34.6% of pts; second cancers were reported in 11.5%, 11.2% and 18.5% of pts, respectively. Conclusion This is the first phase 3 trial comparing the main paradigms of continuous vs fixed-duration targeted therapy of CLL. Early findings indicate that fixed-duration treatment with VO or VI are non-inferior to continuous treatment with I and may therefore represent the preferred treatment option for pts with previously untreated CLL.

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.

Expression of CD2, CD25 and/or CD30 in extracutaneous mast cells (MC) is a minor diagnostic criterion for systemic mastocytosis (SM) in the classification of the World Health Organization and International Consensus Classification. So far, it remains unknown whether expression of these antigens on MC is of prognostic significance in SM. We performed a retrospective multi-center study of patients with SM using the data set of the registry of the European Competence Network on Mastocytosis, including 5034 patients with various MC disorders. The percentage of CD2-, CD25+ and/or CD30+ MC was considerably lower in patients with indolent SM compared to patients with advanced SM, including aggressive SM and MC leukemia. Whereas CD25 and CD30 expres-sion in MC could not be associated with prognosis, we found that lack of CD2 expression in MC is associated with a significantly reduced overall survival (OS) in patients with SM (p<0.0001). Lack of CD2 was also associated with the presence of extramedullary involvement affecting the spleen, liver, and/or lymph nodes (odds ratio 2.63 compared to SM with CD2+ MC). Together, lack of CD2 expression in MC is an important prognostic marker and indicator of reduced OS and extramedul-lary disease expansion in patients with SM.

ABSTRACT:Certain laboratory abnormalities correlate with subvariants of systemic mastocytosis (SM) and are often prognostically relevant. To assess the diagnostic and prognostic value of individual serum chemistry parameters in SM, 2607 patients enrolled within the European Competence Network on Mastocytosis and 575 patients enrolled within the German Registry on Eosinophils and Mast Cells were analyzed. For screening and diagnosis of SM, tryptase was identified as the most specific serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, β2-microglobulin, lactate dehydrogenase (LDH), albumin, vitamin B12, and C-reactive protein (P < .001). With regard to subvariants of AdvSM, an elevated LDH of ≥260 U/L was associated with multilineage expansion (leukocytosis, r = 0.37, P < .001; monocytosis, r = 0.26, P < .001) and the presence of an associated myeloid neoplasm (P < .001), whereas tryptase levels were highest in mast cell leukemia (MCL) vs non-MCL (308μg/L vs 146μg/L, P = .003). Based on multivariable analysis, the hazard-risk weighted assignment of 1 point to LDH (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.1-4.0; P = .018) and 1.5 points each to β2-microglobulin (HR, 2.7; 95% CI, 1.4-5.4; P = .004) and albumin (HR, 3.3; 95% CI, 1.7-6.5; P = .001) delineated a highly predictive 3-tier risk classification system (0 points, 8.1 years vs 1 point, 2.5 years; ≥1.5 points, 1.7 years; P < .001). Moreover, serum chemistry parameters enabled further stratification of patients classified as having an International Prognostic Scoring System for Mastocytosis-AdvSM1/2 risk score (P = .027). In conclusion, serum chemistry profiling is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.

Mastocytosis is a heterogeneous disorder characterized by abnormal mast cell accumulation, in which the clinical severity may be explained by distinct molecular mechanisms. This study aimed to explore plasma protein biomarkers associated with systemic mastocytosis subtypes, as well as the cellular origin of the identified proteins. Plasma samples from patients with mastocytosis, including cutaneous mastocytosis (CM), indolent systemic mastocytosis (ISM), and advanced systemic mastocytosis (AdvSM), and a reference group of patients with polycythemia vera, were analyzed by Proximity Extension Assay technology targeting 275 proteins. Furthermore, potential cellular origin was explored using an available single-cell RNA-sequencing data set generated from patients with ISM. The study cohort included 16 patients with CM, 92 patients with systemic mastocytosis (ISM, n = 80; AdvSM, n = 12), and 60 patients with polycythemia vera. A principal component analysis based on 275 plasma proteins revealed one cluster of patients with CM and ISM that was separated from patients with AdvSM. Up to 29 proteins were associated with distinct severe activity in patients with systemic mastocytosis (ISM versus AdvSM), including IL-1 receptor type 1 (IL-1RT1) and tumor necrosis factor ligand superfamily member 13B (TNFSF13B) (q < 0.01). Furthermore, single-cell RNA-sequencing analysis from ISM-derived bone marrow cells revealed that the mRNA for the identified proteins was not exclusive of mast cells. Distinct plasma protein profiles show potential to refine ISM and AdvSM diagnoses, possibly reflecting differences in pathogenic mechanisms and diverse clinical manifestations.

AbstractBackgroundChronic lymphocytic leukemia (CLL) is a heterogeneous disease. Whereas some patients have an indolent disease, others experience an aggressive course and early death. Our aim was to investigate if modifiable and non‐modifiable medical history and lifestyle factors prior to diagnosis had an impact on the natural course of the disease.MethodIn 1154 CLL patients, we assessed if the weight, physical activity, smoking, and alcohol consumption or non‐modifiable characteristics including family history of lymphoid malignancy and medical history were associated with time‐to‐first‐treatment (TTFT) and adjusted all results for the CLL‐International Prognostic Index (CLL‐IPI).ResultsTTFT was shorter for patients with high/very high‐risk CLL‐IPI than those with low/intermediate risk CLL‐IPI. In the adjusted analysis we did not find additional impact on TTFT besides CLL‐IPI from any environmental characteristics assessed.ConclusionsWe found limited impact of environmental factors on the natural course of CLL (measured as the TTFT in treatment naïve patients) providing valuable knowledge, and potential relief, to share with patients at the time of diagnosis.

BACKGROUND:Hypersensitivity reactions (HR) are common in mastocytosis. However, little is known about triggers and risk factors. The registry of the European Competence Network on Mastocytosis (ECNM) enables reliable studies in a larger cohort of mastocytosis patients. We assessed prevalence, triggers and risk factors of HR in adults with mastocytosis in the ECNM registry. METHODS:Data were collected in 27 ECNM centers. We analyzed potential triggers (Hymenoptera venoms, food, drug, inhalant and others) and risk factors at diagnosis and during follow-up. The study group consisted of 2485 adults with mastocytosis, 1379 women (55.5%) and 1106 men (44.5%). Median age was 48.2 years (range 18-91 years). RESULTS:Nine hundred and forty eight patients (38.1%) reported one or more HR`. Most common triggers were Hymenoptera venoms in cutaneous mastocytosis (CM) and indolent systemic mastocytosis (ISM), whereas in advanced SM (advSM), most common elicitors were drugs, including nonsteroidal anti-inflammatory agents and penicillin. In multivariate analyses, tryptase level < 90 ng/mL, <15% infiltration by mast cells in bone marrow biopsy-sections, and diagnosis of ISM were identified as independent risk factors for HR. For drug-induced HR, prominent risk factors were advSM and high tryptase levels. New reactions were observed in 4.8% of all patients during 4 years follow-up. CONCLUSIONS:HR are mainly triggered by Hymenoptera venoms in patients with CM and ISM and by drugs in patients with advSM. Tryptase levels <90 ng/mL, mast cell bone marrow infiltration <15%, and WHO category ISM are predictors of HR. New HR occur in 4.8% of all patients within 4 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.