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Giant cell arteritis (GCA) is a relapsing large vessel vasculitis with risk of serious ischemic manifestations, including vision loss and vascular damage in the form of large artery stenosis, aneurysms, and dissections. Approximately 50% of patients treated with glucocorticoid (GC) monotherapy and 30% of patients receiving adjunctive therapy with tocilizumab experience disease relapses, often during the first 2 years after diagnosis. Although most relapses in GCA do not involve life‐ or organ‐threatening presentations and can be controlled successfully, frequent relapses may lead to increased prescription of GC and consequent treatment‐related morbidity, in addition to risk of further vascular damage. Emerging data suggest that persistent disease activity may lead to increased vascular morbidity. Additionally, although tocilizumab decreases the frequency of relapses, more than 50% of patients relapse after discontinuation of therapy. Therefore, although interleukin‐6 blockade suppresses disease activity, it does not restore tolerance. In this article, we discuss the practical diagnosis and management of GCA relapses from an expert perspective. Current treatment options for GCA relapses, including those recommended by international guidelines, and novel potential therapies are reviewed.

Background: Positron emission tomography (PET) scan is the imaging modality of choice for initial staging and response assessment of follicular lymphoma (FL). Quantitative parameters such as standardized uptake value (SUV) have been investigated as putative prognosticators in FL, with high baseline SUVmax predicting aggressive disease. To date, there is no data to guide treatment choices in patients (pts) with high SUVmax but with no documented evidence of histologic transformation (HT). Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, are more beneficial than R-Bendamustine (BR) in these pts. Therefore, we aimed to compare the efficacy of frontline R-CHOP and BR in newly diagnosed FL pts based on the SUVmax at baseline PET (bPET). Patients and Methods: Pts with newly diagnosed, biopsy-proven FL1-2 and FL3A who had a bPET scan and who received either first-line R-CHOP or BR within 6 months of diagnosis between 2002 and 2022 were evaluated. Analysis was restricted to pts with age < 70 years to reduce confounding of age with treatment selection. Cohorts included were the FOLL12 (n=562, Luminari et al JCO 2022) and the R-chemotherapy arm of the RELEVANCE (n=216, Morschhauser et al NEJM 2018) clinical trials, the prospectively enrolled Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts (n=288) and a retrospective cohort from 13 Australian centers (n=219). Choice of chemotherapy regimen was per treating physician. Maintenance was per protocol (FOLL12/RELEVANCE) or per treating physician (MER/LEO/Australia). Event-free survival (EFS) and overall survival (OS) were defined as time from treatment initiation to progression, relapse, retreatment or death; both were censored at 72 months due to varying follow-up across cohorts. SUVmax was grouped by tertile within each cohort to account for potential differences in SUVmax distributions and patient populations across cohorts. Kaplan Meier curves and multivariable Cox models cohort-stratified and adjusted for clinical factors (FLIPI, ECOG PS, age, grade 3A) were used to evaluate outcomes. Results: The median age at diagnosis was 57 years (IQR 49-64). 651 (51%) pts were treated with R-CHOP and 634 (49%) with BR. Within the study cohorts, there was a prevalence of cases receiving BR compared to R-CHOP in the Australian (90% vs 10%) and MER/LEO (68% vs 32%) cohorts, while the opposite was observed in the RELEVANCE (16% vs 84%) and FOLL12 (37% vs 63; p<0.001) trials. Pts receiving R-CHOP were slightly younger (median 56 vs 58 years, p=0.005), more frequently had grade 3A (17% vs 7%, p<0.001), elevated LDH (27% vs 22%, p=0.029), bulky disease > 7 cm (44% vs 37%, p=0.019), lower ECOG PS (PS >1 7% vs 13%, p<0.001), and higher rate of high risk FLIPI (37% vs 30%, p=0.005). Baseline SUVmax was slightly lower in R-CHOP (median 10.7, IQR 7.9-14.9) vs BR (median 11.0, IQR 8.2-14.2) treated pts (p=0.0045). At a median follow-up of 56 months (range, 1-72 months), 415 pts (32%) had an event and 103 (8%) died. Higher SUVmax was not associated with EFS (middle tertile HR=0.96, 95% CI 0.76-1.22; upper tertile HR=0.86, 95% CI 0.68-1.09; p=0.45) or OS (middle tertile HR=1.28, 95% CI 0.80-2.05; upper tertile HR=0.97, 95% CI 0.59-1.59; p=0.44) in multivariable models stratified on cohort and adjusted for treatment and clinical factors. We then compared outcomes by treatment within tertiles of SUVmax. In multivariable models, R-CHOP had modestly inferior EFS to BR in low (HR=1.27, 95% CI 0.84-1.93) and middle tertiles (HR=1.49, 95% CI 0.99-2.25), and modestly superior OS to BR in low (HR=0.59, 95% CI 0.23-1.47) and middle (HR=0.79, 95% CI 0.37-1.71) tertiles. Both EFS (HR=1.06, 95% CI 0.71-1.58) and OS (HR=1.02, 95% CI 0.45-2.30) for R-CHOP were similar to BR in the highest tertile. No comparisons identified a statistically significant benefit for either therapy in multivariable models when evaluating SUVmax tertile subsets. Conclusions: In this large multicenter study of newly diagnosed FL pts with bPET who received frontline immunochemotherapy, higher baseline SUVmax was not associated with inferior outcomes after adjusting for treatment and clinical factors. Within the caveats of retrospective studies and confounding of treatment selection, these data provide no clear insights for SUVmax-based therapy selection in first-line follicular lymphoma pts treated with immunochemotherapy.

Introduction Patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) experience progressively worse outcomes with each successive line of therapy; complete response (CR) rates are 44% with third-line (3L), 27% with 4L, and 22% with 5L+ therapies (Ghione P et al. Haematologica 2023). CR duration is particularly important considering the rapid disease progression observed with 3L+ therapies in pts with FL, with especially poor outcomes in those with high-risk features (Liu J et al. Front Oncol 2023; Philips T et al. ASH 2023). In ELM-2 (NCT03888105), odronextamab (an investigational CD20×CD3 bispecific antibody) demonstrated deep and durable responses and generally manageable safety in pts with R/R FL who had received ≥2 prior lines of systemic therapy. Median progression-free survival (PFS) and overall survival (OS) in pts with CR were 28 months (95% CI 23.0-not evaluable [NE]) and not reached (95% CI 40.4-NE), respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 86% of pts (Taszner M et al. EHA 2024). For the current analysis, we present details on the efficacy and safety of 3L+ odronextamab treatment in pts with R/R FL who attained CR in ELM-2, including those with high-risk features. Methods ELM-2 is an ongoing, open-label, multicenter, Phase 2 trial of odronextamab in pts with R/R B-cell non-Hodgkin lymphoma, including a cohort with FL Grade 1-3a. Intravenous odronextamab was administered in step-up doses with steroid prophylaxis during Cycle (C) 1, followed by 80 mg on Days 1, 8, and 15 of C2-4. After C4, dosing continued at 160 mg once every 2 weeks (Q2W); pts switched to Q4W dosing if they had a durable CR for ≥9 months. The primary endpoint was objective response rate (ORR) according to Lugano classification, by independent central review (ICR). Secondary endpoints included CR rate, PFS, OS, duration of response, and safety. Results Primary results in pts evaluable for efficacy and safety (N=128) using the Oct 20, 2023, data cutoff have been reported. Median duration of efficacy follow-up was 20.1 months (95% CI 17.3-27.8). The ORR was 80.5% (103/128 pts; 95% CI 72.5-86.9), and CR rate was 73.4% (94/128; 95% CI 64.9-80.9). Median duration of CR (DOCR) was 25.1 months (95% CI 20.5-NE), and median time to CR was 2.7 months (range 2.3-7.9). Baseline characteristics of pts with CR (n=94) were similar to those of the overall population, and median duration of treatment exposure was 13.8 months (range 1.8-45.0). In total, 88 pts (93.6%) had CR at the first response assessment (~Week 12) and 6 (6.4%) reached CR later, including 3 pts who had stable disease initially. Twenty-eight pts (29.8%) were still receiving treatment at data cutoff, and 66 (70.2%) had discontinued treatment. Of those who discontinued, 42 still had CR at the last response assessment. Primary reasons for treatment discontinuation were disease progression (n=17), TEAEs (n=16 [including 6 pts with COVID-19]), physician decision (n=12), withdrawal by subject (n=11), and death (n=8). All 8 deaths resulted from TEAEs, including COVID-19 in 5 pts. Eighty-five pts (90.4%) with CR had high-risk features (POD24, 48.9%; FLIPI score 3-5, 55.3%; refractory to last treatment, 70.2%); median DOCR and median time to CR in these pts were similar to those in all pts (23.7 months [95% CI 18.2-NE] and 2.7 months [range 2.3-7.9], respectively). At the time of the current analysis, 44 pts with CR by ICR (46.8%) had switched to Q4W dosing, with a median duration of exposure of 17.7 months (range 13.1-45.0). Among these pts, 22 had discontinued treatment at data cutoff due to adverse events (n=7 [including 1 with COVID-19]), physician decision (n=6), death (n=3), withdrawal by subject (n=3), progressive disease (n=2), and an “other” reason (n=1). Conclusions Pts with R/R FL and CR to 3L+ odronextamab treatment in ELM-2 had a median DOCR of 25.1 months that was prolonged beyond the median duration of treatment exposure (13.8 months). Almost half (46.8%) of pts proceeded to monthly odronextamab administration, with a median duration of treatment exposure of 17.7 months. These data show the sustainability of CR in pts with FL treated with 3L+ odronextamab, including in those with high-risk features. The safety profile of odronextamab was generally manageable in the overall population, including in pts with CR, despite their prolonged drug exposure. These findings support the potential of odronextamab as a treatment for R/R FL.

Background: Although advanced stage cHL typically has excellent disease outcomes, 20-30% of patients (pts) experience treatment failure. In addition, decision-making is challenging given varying treatment options and incomplete prognostic data across the disease course. Pre-treatment factors, such as those incorporated into the Advanced Stage Hodgkin Lymphoma International Prognostication Index (A-HIPI), predict 5 year (y) overall survival (OS) and progression-free survival (PFS) (Rodday JCO 2023). Other than interim PET (iPET) results, it is unknown what factors influence cHL disease states mid-therapy. Using multistate modeling (MSM) and individual pt data from the HoLISTIC Consortium, we refined prognostication across the cHL disease course, specifically assessing the relationships between A-HIPI, iPET and end of treatment (EOT) response, and whether the A-HIPI and iPET provide independent prognostic information. Methods: We analyzed 1240 pts aged 18-65y with newly diagnosed Stage IIB, III or IV cHL treated on 2 advanced stage PET-adapted trials (RATHL, SWOG0816). All pts first received 2 cycles of ABVD; those with a negative iPET (Deauville score (DS) ≤3) received ABVD or AVD, and those with a positive iPET (DS >3) received BEACOPP. In contrast to other methods, MSMs incorporate multiple disease states into one model, account for censoring and competing risks, and estimate transitions between disease states using different covariates. Our MSM had 6 states: diagnosis, negative iPET, positive iPET, EOT non-progression (e.g., DS ≤ 3), treatment failure, and death. Treatment failure included progression or relapse. All pts start at the diagnosis state and can transition to other states without return to prior states. Transition states with <5 events were excluded. The MSM was estimated using a multivariable Cox model with censoring at 5y. Covariates were the 5y PFS A-HIPI (comprised of stage and continuous age, lymphocyte count and albumin), which was included for all transitions, and iPET, which was included for transitions from EOT non-progression and from treatment failure. Higher scores on the 5y PFS A-HIPI indicate lower risk of progression or death; the A-HIPI was modeled for a 1 standard deviation (SD) increase. We calculated probabilities of 5y treatment failure for 4 sample pts based on low (70) and high (85) A-HIPI scores, positive and negative iPET, and EOT non-progression. Results: Median age was 33y (Q1=25, Q3=45), 56% were male, 23% were stage IIB, 40% III and 37% IV, and mean A-HIPI was 77 (SD=7). Median follow-up was 75 months (Q1=53, Q3=92). At iPET, 80% (95% CI 78%, 83%) were negative and 16% (95% CI 14%, 18%) were positive. At EOT, 90% (95% CI 89%, 92%) were in the non-progression state. At 5y, 75% (95% CI 73%, 78%) were in the non-progression state, 16% (95% CI 14%, 19%) had experienced treatment failure, and 9% (7%, 11%) had died. Better A-HIPI scores (per SD) were associated with lower rates of transitioning from diagnosis to positive iPET (HR=0.80, p<0.01) and from positive iPET to treatment failure (HR=0.58, p=0.04). Better A-HIPI scores (per SD) were also associated with lower rates of transitioning from EOT non-progression to treatment failure (HR=0.78, p<0.01) and from treatment failure to death (HR=0.64, p<0.01), adjusting for iPET. Positive iPET was associated with an increased rate of transitioning from EOT non-progression to treatment failure (HR=1.90, p<0.01), adjusting for A-HIPI. The probability of 5y treatment failure for 4 sample pts was: 25% for low A-HIPI and positive iPET; 20% for high A-HIPI and positive iPET; 13% for low A-HIPI and negative iPET; and 12% for high A-HIPI and negative iPET. Conclusions: We created a novel MSM that refines prognostication across the cHL disease course by incorporating pre- and post-treatment factors (e.g., iPET) to estimate transitions to future disease states. Although the A-HIPI was developed using pre-treatment factors to predict 5y OS and PFS, we found that it was also associated with transitions to interim disease states, including iPET and EOT response. The A-HIPI and iPET each provided independent prognostic information, supporting the use of both in estimating cHL outcomes. Future analyses will develop clinical prediction models using MSMs that also incorporate varying frontline and salvage treatments and treatment-specific late effects, with the goal of providing individualized information across the disease course.

Background: Light chain (AL) amyloidosis is a rare and understudied plasma cell disorder. It is caused by abnormal misfolding of monoclonal immunoglobulin light chains, leading to extracellular deposition of amyloid, ultimately resulting in organ dysfunction and death. Since AL amyloidosis is uncommon, therapies are adapted from the more common plasma cell disorders like multiple myeloma. Daratumumab, a monoclonal antibody targeting CD38, was first tested in several prospective and retrospective studies in AL patients with relapsed refractory disease. The ANDROMEDA study (Kastritis E et al, NEJM 2021) established daratumumab in combination with CyBorD (Cyclophosphamide-Bortezomib-Dexamethasone) followed by daratumumab maintenance as the new standard of care compared to CyBorD alone for newly diagnosed patients. Consequently, daratumumab maintenance has become universally offered to all newly diagnosed AL amyloidosis patients. Notably, there was no second randomization before the initiation of maintenance therapy in ANDROMEDA. Hence, a critical question that remains is whether the superior efficacy observed in the investigational arm of the ANDROMEDA trial is solely a result of the addition of daratumumab during the induction phase or if the maintenance phase contributed to the favorable outcomes in the investigational arm. We hypothesize that a shorter duration of maintenance would prove non-inferior to the standard duration of daratumumab maintenance in patients with AL amyloidosis that have responded to Daratumumab-CyBorD induction. To answer this question we are conducting a pragmatic phase 2 randomized trial assessing the optimal duration of daratumumab maintenance in patients with AL amyloidosis who have responded to Daratumumab-CyBorD induction. Study Design, Patients and Methods: We use broadened eligibility criteria consistent with pragmatic trial design. The estimated total enrollment is up to 96 patients. The main eligibility criteria are patients with biopsy-proven AL Amyloidosis who have completed 6 cycles of Dara-CyBorD-based induction treatment and achieved an adequate response to induction (defined as hematological complete response (CR), hematological very good partial response (VGPR), or hematological partial response (PR) with at least one organ response). Patients in whom bortezomib and/or cyclophosphamide were omitted from induction due to toxicity concerns or adverse effects are allowed. The major exclusion criteria are patients who were concomitantly diagnosed with multiple myeloma based on International Myeloma Working Group (IMWG) criteria. This phase II, open-label, multicenter trial (NCT05898646) randomizes patients who have attained an adequate response to 6 cycles of Dara-CyBorD-based induction in a 1:1 ratio, using a dynamic allocation procedure that balances the marginal distributions of the stratification factors (age, cardiac stage, and t(11;14) status). Randomization is to either single-agent daratumumab maintenance of 6 cycles duration (experimental arm) or 18 cycles of daratumumab maintenance (control arm) (cycle = 28 days). Treatment is allowed to be given at a local facility After completing maintenance treatment, patients will follow up every 3 months for up to 36 months from registration. The primary endpoint of the trial is to evaluate the non-inferiority of a shorter (6 cycles) daratumumab maintenance measured by event-free survival (EFS) compared to the standard maintenance of 18 cycles in newly diagnosed AL amyloidosis who receive 6 cycles of daratumumab-CyBorD based induction. EFS in this study is defined as time from registration to any of the following events: hematological progression, organ progression, subsequent anti-plasma cell therapy in the absence of hematological progression but with persistent organ dysfunction or death, whichever occurs first. Secondary endpoints are depth of hematological and organ response, bone marrow measurable residual disease negativity rate, duration of response, quality of life, and survival. By investigating whether a shorter duration of maintenance is non-inferior to the standard duration, we aim to inform clinical practice and potentially reduce the toxicities associated with prolonged maintenance therapy, including hypogammaglobulinemia, recurrent infections, the need for intravenous gammaglobulin replacement, and financial toxicity.

Background Conventional thrombosis risk stratification in polycythemia vera (PV) considers age > 60 years and thrombosis history for assignment to low (no risk factor) or high (at least 1 risk factor) risk category (J Clin Oncol.2011;29(6):761-70). The current study exclusively focused on low-risk PV with the following objectives: i) estimate the incidence of arterial and venous thrombosis; ii) examine the prognostic relevance of clinical and genetic risk factors for thrombosis; and iii) assess the impact of treatment on thrombosis risk. Methods Patients were retrospectively recruited from the Mayo Clinic, USA, and University of Florence, Italy, PV databases. Diagnosis was according to the International Consensus Classification criteria (Blood 2022;140:1200). Only first major arterial (AT) and unprovoked venous thrombosis (VT) were considered. Conventional statistical methods were applied (JMP Pro 17.0.0, SAS Institute, Cary, NC, USA). Results Mayo Clinic cohort A total of 346 patients with low-risk PV were considered: median age 49 years; males 54%; median hemoglobin 17.7 g/dl; median leukocyte count 10.9 x 109/L; leukocyte count >11 x 109/L 49%; median platelet count 471 x 109/L; cardiovascular (CV) risk factors 47%; hypertension 29%; hyperlipidemia 20%; smoking history 12%; diabetes mellitus 5%. Most frequent mutations, other than JAK2, were ASXL1 (13%) and TET2 (13%). Median follow-up was 13.4 years (1-52) (4,636 patient-years) during which 25 (7%) AT and 20 (6%) VT were documented. The corresponding incidence rates were 5.4 and 4.3 per 1,000 patient-years. In multivariable logistic regression analysis, baseline hemoglobin >17.5 g/dl in women or >20 g/dl in men (15% vs 4%; OR 5.1; p<0.01) and absence of leukocytosis >11 x 109/L (10% vs 4%; OR 2.9; p=0.02) were associated with increased risk of AT; in addition, diabetes mellitus (19% vs 7%; OR 3.9; p=0.06), showed borderline significance; overall incidence of AT was 20% in the presence of ≥2 risk factors (n=61), 7% in the presence of one risk factor (n=177), and 1% in the absence of all three risk factors (n=108; p<0.01). Multivariable analysis for arterial thrombosis-free survival (TFS) confirmed the predictive performance of these risk factors: hemoglobin thresholds (HR 4.4; p<0.01); absence of leukocytosis >11 x 109/L (HR 2.7; p=0.03); and diabetes (HR 2.8; p=0.09); 20-year cumulative incidence of AT was 32% in the presence of ≥2 risk factors and 7% otherwise (p<0.01). In multivariable analysis, smoking history was found to be surprisingly protective against VT (0% vs. 7%; p=0.02) while female gender was associated with a borderline higher risk (8% vs 4%; OR 2.2; p=0.09); VT incidence rates were 9% in the presence of both risk factors (n=144), 4% with one risk factor (n=172), and 0% in the absence of both risk factors (n=40; p=0.02); 20-year cumulative incidence of VT was 10% in the presence of both risk factors and 3% otherwise (p=0.03). ASXL1 and TET2 mutations did not appear to modify the risk of either VT (p=0.59) or AT (p=0.66). Treatment at diagnosis included aspirin and cytoreductive therapy in 63% and 24% of patients, respectively. Aspirin but not cytoreductive therapy was associated with a lower incidence of AT (5% vs 11%; 2.3 vs 3.0 per 1,000 patient-years; p=0.04) and VT (4% vs 10%; 1.9 vs 2.8 per 1,000 patient-years; p=0.03). Thrombosis-free survival was not influenced by documented treatment at diagnosis or at the time of event (p>0.1). University of Florence cohort A total of 284 low-risk PV patients were followed for a median of 9.1 years (1-38) with 19 (7%) AT and 24 (8%) VT events recorded; the corresponding incidence rates were 7.4 and 9.3 per 1,000 patient-years. In this Florence cohort, risk factors for AT were diabetes mellitus (HR 3.9), hyperlipidemia (HR 3.8) and advanced age, with only age remaining significant during multivariable analysis (p=0.03). Predictors of VT included hyperlipidemia (HR 4.2) and hypertension (HR 2.1). Treatment with aspirin or cytoreductive therapy did not impact thrombosis-free survival (p>0.1). Conclusion The current study confirms the infrequent occurrence of AT and VT in low-risk PV but also exposes the challenges in identifying risk factors that are reproducible in different but otherwise well-characterized patient cohorts. Discrepancies were also apparent in retrospective comparison of treatment effects on thrombosis, which reinforces the need for prospective studies.

Background Survival risk models in essential thrombocythemia (ET) include the International Prognostic Scoring System (IPSET; Blood 2012;120:1197) and the more recently described “triple-A” prognostic score that considers Age and absolute neutrophil (ANC) and lymphocyte (ALC) counts, as risk variables (AJH 2023;98:1829). Monocytosis, defined by absolute monocyte count (AMC) of ≥0.8 x 109/L, was recently reported to be associated with inferior survival in polycythemia vera (ASH 2024 abstract). The current study examined the prognostic contribution of monocytosis in ET, in the context of other clinical and genetic risk factors. Methods Study patients were recruited from Mayo Clinic (USA) databases, based on availability of information on ANC, ALC, and AMC (N=649). Diagnostic criteria were according to the International Consensus Classification (Blood 2022;140:1200). Mutations were screened by next-generation sequencing (NGS). Conventional statistical methods were employed (JMP Pro 17.0.0, SAS Institute, Cary, NC, USA) and optimal cut-points for age, ANC, ALC, and AMC were determined by Receiver Operating Characteristic (ROC) analysis. Akaike Information Criterion (AIC) and ROC plots were used to estimate predictive accuracy of risk models. Results A total of 649 patients (median age 60 years; females 65%) were informative for AMC, ANC, and ALC, with median (range) values of 0.6 x 109/L (0.2-2.5), 5.7 x 109/L (1.5-26.5), and 1.9 (0.4-5.7), respectively. At presentation, IPSET risk distribution was low in 34%, intermediate 47%, and high 19%; triple-A risk distribution was low 21%, intermediate-1 50%, intermediate-2 13%, and high 16%; driver mutation distribution was 63.8% JAK2, 24.0% CALR, 3.7% MPL, and 8.5% triple-negative; median for platelets were 728 x 109/L, hemoglobin 13.9 g/dL, and leukocytes 8.5 x 109/L ; leukocytosis (leukocytes ≥11 x 109/L) was documented in 18.8% of patients, palpable splenomegaly 7%, arterial thrombosis (AT) history 14.5%, venous thrombosis (VT) history 9.2%, and major hemorrhage 7.8%. At median follow-up of 7 years (range 0.02-31.4), 146 (22.5%) deaths, 52 (8%) fibrotic progressions, 22 (3.4%) leukemic transformations, 71 (11%) AT events, 36 (5.6%) VT events, and 64 (10%) major bleeds were recorded. In age-adjusted univariate analysis, higher AMC was significantly associated with inferior survival, with a ROC determined cutoff value of ≥0.8 x 109/L (N=154; 24%); significance was sustained (HR 2.3; p<0.01) during multivariable analysis (MVA) that also identified age >70 years (HR 16.6; p<0.01), age 50-70 years (HR 4.3; p<0.01), ANC ≥8 x 109/L (HR 1.9; p<0.01), ALC <1.7 x 109/L (HR 1.8; p<0.01), and AT history (HR 1.6; p=0.01). A similar MVA conducted on an external cohort from the University of Florence (N=514) confirmed the significant contribution from all of these risk variables, except AT (p=0.8). An HR-based 4-variable prognostic model based on Age >70 years (4 points) or 50-70 years (2 points), AMC ≥0.8 x 109/L (1 point), ANC ≥8 x 109/L (1 point), and ALC <1.7 x 109/L (1 point), henceforth referred to as the AAA+A model, was subsequently developed using the Mayo Clinic cohort and validated by the Florence cohort: Low (0-1 points; N= 180; median not reached), intermediate-1 (2-3 points; N=266; median 21.6 years), intermediate-2 (4-5 points; N=151; median 12.2 years), and high (6-7 points; N=52; median 8.7 years); HR values were 2.1 for high vs. intermediate-2, 5.4 for intermediate-2 vs. intermediate-1, and 3.8 for intermediate-1 vs. low (p<0.001in all instances). The 20-year survival predictive performance of AAA+A (AIC 131; AUC 0.88) was superior to that of AAA (AIC 143; AUC 0.85) and IPSET (AIC 149; AUC 0.84). In MVA that included AAA+A risk variables, AMC ≥0.8 x 109/L (p=0.04) and ALC <1.7 x 109/L (p=0.06) appeared to affect leukemia-free survival and ANC ≥8 x 109/L (p=0.04) myelofibrosis-free survival. In univariate analysis, AMC ≥0.8 x 109/L was associated with AT (p=0.03) but not VT (p=0.14) history and showed borderline significance for venous (p=0.09) and arterial (p=0.07) thrombosis-free survivals; however, significance was lost during MVA. Conclusions: Monocytosis is an adverse prognostic factor in ET and its inclusion as a risk variable enhances the predictive performance of the AAA risk model and is equally simple to apply worldwide. Analyses that include mutations will be presented at meeting.

Background: The JAK2 46/1, also referred to as the GGCC, haplotype, is represented by 4 main SNPs spanning a region of 250kb in chr9 including the JAK2 gene, that are in complete linkage disequilibrium. The GGCC haplo was found to confer susceptibility to JAK2 mutated myeloproliferative neoplasms (MPN) (Jones AV, 2009; Olcaydu D, 2009; Kilpivaara O, 2009) while association with JAK2-wildtype MPN remains controversial (Pardanani A, 2010; Jones AV, 2010; Guglielmelli P, 2010; Trifa A, 2016). The GGCC haplo was also found enriched in MPN pts with splancnic vein thrombosis (SVT) (Smalberg JH, 2011), and to correlate with higher JAK2V617F variant allele frequency (VAF) (Alvarez-Larran, A, 2012). Nullizigosity for GGCC haplo was associated with reduced survival (OS) in pts with myelofibrosis (MF) (Tefferi A, 2019), but no information on the impact of GGCC haplo status with phenotype and outcome in PV is available. Aim: To assess the clinical correlates and the prognostic significance of GGCC haplo status in a large cohort of pts with PV. Pts and Methods: A total of 399 PV pts, all JAK2V617F mutated, diagnosis revised according to 2022 ICC criteria, were genotyped for 46/1 haplotype by PCR allele discrimination with rs12343867 (with the “C” allele standing for 46/1 haplotype). Results: A total of 301 pts (75.4%) had the C allele, of which 143 (47.5%) were CC homo and 158 (52.5%) CT hetero; 98 (24.6%) were nullizygous for GGCC (TT). Since preliminary analysis disclosed no significant difference between CT and TT haplotype for all variables considered, homozygous CC pts were compared to TT+CT. The CC haplotype was associated with higher leukocytes (median 11.3x10e9/L vs 9.6, p<.001), higher hemoglobin (18.4 g/dL vs 17.5, p<.001), lower platelets (441x10e9/L vs 514, p=.002) more aquagenic pruritus (51.8% vs 33.2%, p=.001), and higher JAK2VAF (60.8+-24.8% vs 36.8+-19.7%, p<.001) at diagnosis. Pts with a VAF >50% were 69% in CC versus 24.1% in TT+CT pts (p<.001). ASXL1 mutations were enriched among CC pts (20.3% vs 9.4%, p=0.04), otherwise no difference regarding additional myeloid mutations was noted. All above differences remained significant when considering CC versus TT and CT separately. More pts with CC haplotype suffered from venous thrombosis (VT) during the FU (16.1% vs 4.3%, p<.001), no difference was noted for arterial thrombosis nor for splancnic vein thrombosis. VT-FS by Kaplan Meyer was significantly shorter (p<.001) in CC pts; the rate of VT at 5, 10, 15y after diagnosis, was 5.5%, 12%, 20.2% for CC versus 2.6%, 3.4%, 6.4% for TT+CT, respectively (all p<.001). In multivariable analysis, including JAK2VAF >50%, age >60y, history of VT, WBC >15x10e9/L, only CC haplo remained significant (HR 3.6, 95%CI 1.4-9.5, p=.009). Progression to post-PV MF occurred in 81 pts (20.3%), significantly more among CC (n=45, 31.5%) than TT+CT (n=36; 14.1%; p<.001). Myelofibrosis-FS was significantly shorter in CC vs other genotypes (p=.02). However, in multivariable analysis, only BM fibrosis G1 remained significant (HR 3.2, 1.7-5.9; p<.001). Evolution to blast-phase occurred in 13 pts (3.2%), 9 (6.3%) with CC haplo vs 4 TT+CT (1.6%; p=.01). During the follow-up, 102 pts (25.5%) died, 50 (35%) CC and 52 TT+CT (20.3%; p=.001). In multivariable analysis, including MIPSS-PV variables (Tefferi A 2020), the CC haplo remained significant (HR 1.8, 1.04-3.2, p=.03) together with age (HR 3.0, 1.6-5.7; p<.001), WBC (HR 2.6, 1.3-4.8; p=.004), and thrombosis history (HR 1.9, 1.0-3.7; p=.03). Conclusions. Homozygosity for the 46/1 or CC haplotype contributes to the phenotype diversity of PV, in part possibly mediated by associated higher JAK2V67F VAF, and predicts for incident VT and shorter OS. Supported by AIRC, 21267; MIUR,2022F4WMR3; IHM, PNRR-MAD-2022-12376695

Background In 2013, we published the first International Working Group (IWG) risk model for survival in polycythemia vera (PV), which included 3-tiered age categories, leukocytosis (≥15 x 109/L), and venous thrombosis, as risk variables (Leukemia. 2013;27:1874). In the current study, we examined the individual prognostic contribution from specific leukocyte components and mutations, in order to construct a more contemporary clinical risk model in PV and assess its interaction with genetic risk factors. Methods Study patients were retrospectively recruited from the Mayo Clinic, USA (N=1,007) and the University of Florence, Italy (N=514), in order to serve as discovery and validation cohorts, respectively. Diagnostic criteria were according to the International Consensus Classification (Blood 2022;140:1200). Mutations were screened by next-generation sequencing (NGS). Conventional statistical methods were employed (JMP Pro 17.0.0, SAS Institute, Cary, NC, USA) and optimal cut-points for age, absolute neutrophil (ANC), lymphocyte (ALC), and monocyte (AMC) counts were determined by Receiver Operating Characteristic (ROC) analysis. Akaike Information Criterion (AIC) and ROC plots were used to estimate predictive accuracy. Results Presenting features in the Mayo discovery cohort (N=1,007) included: median age 62.2 years; males 50.7%; median leukocyte count 10.8 x 109/L; leukocyte count ≥15 x 109/L 19%; palpable splenomegaly 32%; pruritus 34%; diabetes 16%; hypertension 61%; arterial thrombosis 14%; and venous thrombosis 14%. ANC, AMC, and ALC information was available in 736 patients with respective median (range) values of 7.6 (1.6-30), 0.6 (0-4.1), and 1.54 (0.19-6.9) x 109/L. At a median follow-up of 8.9 years for the Mayo discovery cohort, 372 (37%) deaths, 46 (4.6%) leukemic transformations, and 200 (20%) fibrotic progressions were recorded. Multivariable analysis (MVA) employing ROC-determined cutoff values revealed adverse survival impact for age >70 years (HR 18.3; p<0.01), age 50-70 years (HR 4.9; p<0.01), AMC ≥0.8 x 109/L (HR 1.5; p<0.01), ANC ≥8 x 109/L (HR 1.5; p<0.01), arterial thrombosis (HR 1.5; p<0.01), diabetes (HR 1.4; p=0.04), and male sex (HR 1.3; p=0.05). A similar MVA applied to the Florence validation cohort (N=514) confirmed significance for age (p<0.01), ANC (p<0.01), AMC (p=0.04), and arterial thrombosis (p<0.01), but not for male sex (p=0.8) or diabetes (p=0.15). Accordingly, age >70 years (4 points), age 50-70 years (2 points), ANC ≥8 x 109/L (1 point), AMC ≥0.8 x 109/L (1 point), and AT (1 point) were included in a revised IWG survival model using the Mayo cohort and validated by the Florence cohort: very low risk (0 points; N=67; median 37 years), low risk (1 point; N=55; median 29.2 years), intermediate risk (2-3 points; N=308; median 20.2 years), high risk (4-5 points; N=217; median 11.5 years), and very high risk (6-7 points; N=88; median 6.3 years). 20-year survival prediction performance of the revised IWG model (AIC 204; AUC 0.88) was superior to that of the 2013 IWG version (AIC 350; AUC 0.86). Mutation information at diagnosis/chronic phase was available in 270 Mayo patients: ASXL1 10%; SRSF2 4%, IDH2 2%, TP53 2%, RUNX1 1.4%. MVA of mutations identified SRSF2 (p<0.01), IDH2 (p=0.01), and ASXL1 (p=0.05), as risk factors for overall survival. The presence of any one adverse mutation was more likely in patients with AMC ≥0.8 x 109/L (24% vs. 7% incidence; p<0.01). In all-inclusive MVA, independent risk factors for OS were age >70 years (HR 14.7), age 50-70 years (HR 6.2), any one adverse mutation (HR 3.4), and ANC ≥8 x 109/L (HR 2.3), but not AMC ≥0.8 x 109/L (p=0.9), arterial thrombosis (p=0.24), or abnormal karyotype (p=0.4). Leukemia-free survival was adversely affected by SRSF2, RUNX1, TP53, and ASXL1 mutations and myelofibrosis-free survival by SRSF2 mutation. Conclusions: The currently proposed revised IWG risk model for survival in PV is globally applicable and based on four easily accessible clinical variables (Age, ANC, AMC, and arterial thrombosis). NGS-derived mutation information overshadows the prognostic relevance of monocytosis, provides additional prognostic information for overall survival, and assists in predicting leukemic and fibrotic transformations.