Logo: to the web site of Uppsala University

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.

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.

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.

Background

Chronic 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.

Method

In 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).

Results

TTFT 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.

Conclusions

We found limited impact of environmental factors on the natural course of CLL (measured as the TTFT in treatment na & iuml;ve patients) providing valuable knowledge, and potential relief, to share with patients at the time of diagnosis. How patients have lived their life (i.e. degree of physical activity, smoking and alcohol consumption) has no impact on the natural course of chronic lymphocytic leukemia (CLL), measured as time to first treatment, while CLL-international prognostic index (IPI) and its components strongly predicts prognosis. image

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.

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.

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 speci fic serum parameter. For differentiation between indolent and advanced SM (AdvSM), the following serum parameters were most relevant: tryptase, alkaline phosphatase, beta 2-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 (308 μg/L vs 146 μg/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 pro filing is a crucial tool in the clinical practice supporting diagnosis and prognostication of SM and its subvariants.

Background Indolent systemic mastocytosis (ISM) is a clonal mast-cell disease driven by the KIT D816V mutation. We assessed the efficacy and safety of avapritinib versus placebo, both with best supportive care, in patients with ISM. Methods We randomized patients with moderate to severe ISM (total symptom score [TSS] of >= 28; scores range from 0 to 110, with higher numbers indicating more severe symptoms) two to one to avapritinib 25 mg once daily (n=141) or placebo (n=71). The primary end point was mean change in TSS based on the 14-day average of patient-reported severity of 11 symptoms. Secondary end points included reductions in serum tryptase and blood KIT D816V variant allele fraction (>= 50%), reductions in TSS (>= 50% and >= 30%), reduction in bone marrow mast cells (>= 50%), and quality of life measures. Results From baseline to week 24, avapritinib-treated patients had a decrease of 15.6 points (95% CI, -18.6 to -12.6) in TSS compared to a decrease of 9.2 points (-13.1 to -5.2) in the placebo group; P<0.003. From baseline to Week 24, 76/141 patients (54%; 45% to 62%) in the avapritinib group compared to 0/71 patients in the placebo group achieved a >= 50% reduction in serum tryptase level; P<0.001. Edema and increases in alkaline phosphatase were more common with avapritinib than placebo; there were few treatment discontinuations because of adverse events. Conclusions In this trial, avapritinib was superior to placebo in reducing uncontrolled symptoms and mast-cell burden in patients with ISM. The long-term safety and efficacy of this approach for patients with ISM remain the focus of the ongoing trial. (Funded by Blueprint Medicines Corporation; ClinicalTrials.gov number, NCT03731260.)

Recent evidence suggests that the prognostic impact of gene mutations in patients with chronic lymphocytic leukemia (CLL) may differ depending on the immunoglobulin heavy variable (IGHV) gene somatic hypermutation (SHM) status. In this study, we assessed the impact of nine recurrently mutated genes (BIRC3, EGR2, MYD88, NFKBIE, NOTCH1, POT1, SF3B1, TP53, and XPO1) in pre-treatment samples from 4580 patients with CLL, using time-to-first-treatment (TTFT) as the primary end-point in relation to IGHV gene SHM status. Mutations were detected in 1588 (34.7%) patients at frequencies ranging from 2.3-9.8% with mutations in NOTCH1 being the most frequent. In both univariate and multivariate analyses, mutations in all genes except MYD88 were associated with a significantly shorter TTFT. In multivariate analysis of Binet stage A patients, performed separately for IGHV-mutated (M-CLL) and unmutated CLL (U-CLL), a different spectrum of gene alterations independently predicted short TTFT within the two subgroups. While SF3B1 and XPO1 mutations were independent prognostic variables in both U-CLL and M-CLL, TP53, BIRC3 and EGR2 aberrations were significant predictors only in U-CLL, and NOTCH1 and NFKBIE only in M-CLL. Our findings underscore the need for a compartmentalized approach to identify high-risk patients, particularly among M-CLL patients, with potential implications for stratified management.

Mast cell leukemia (MCL) is a rare subtype of systemic mastocytosis defined by >= 20% mast cells (MC) on a bone marrow aspirate. We evaluated 92 patients with MCL from the European Competence Network on Mastocytosis registry. Thirty-one (34%) patients had a diagnosis of MCL with an associated hematologic neoplasm (MCL-AHN). Chronic MCL (lack of C-findings) comprised 14% of patients, and only 4.5% had "leukemic MCL" (>= 10% circulating MCs). KIT D816V was found in 62/85 (73%) evaluable patients; 9 (11%) individuals exhibited alternative KIT mutations, and no KIT variants were detected in 14 (17%) subjects. Ten evaluable patients (17%) had an abnormal karyotype and the poor-risk SRSF2, ASXL1, and RUNX1 (S/A/R) mutations were identified in 16/36 (44%) patients who underwent next-generation sequencing. Midostaurin was the most common therapy administered to 65% of patients and 45% as first-line therapy. The median overall survival (OS) was 1.6 years. In multivariate analysis (S/A/R mutations excluded owing to low event rates), a diagnosis of MCL-AHN (hazard ratio [HR], 4.7; 95% confidence interval [CI], 1.7-13.0; P = .001) and abnormal karyotype (HR, 5.6; 95% CI, 1.4-13.3; P = .02) were associated with inferior OS; KIT D816V positivity (HR, 0.33; 95% CI, 0.11-0.98; P = .04) and midostaurin treatment (HR, 0.32; 95% CI, 0.08-0.72; P = .008) were associated with superior OS. These data provide the most comprehensive snapshot of the clinicopathologic, molecular, and treatment landscape of MCL to date, and should help further inform subtyping and prognostication of MCL.