Citations

Abstract Purpose: Inhibitors of the Ataxia telangiectasia and Rad3-related (ATR) protein kinase, a critical component of the DNA damage repair response, have synergistic anti-cancer activity with platinum compounds in preclinical models. We therefore conducted a Phase 2 study of the ATR inhibitor berzosertib+carboplatin vs. docetaxel+carboplatin in metastatic castration-resistant prostate cancer. Patients and Methods: Patients previously treated with at least one androgen receptor pathway inhibitor and taxane underwent mandatory biopsy and were randomized 1:1 to receive Arm A (docetaxel 60 mg/m2+carboplatin AUC4 day 1; or carboplatin AUC5 if not a docetaxel candidate) or Arm B (berzosertib 90 mg/m2 days 2,9+carboplatin AUC5 day 1) every 21 days. The primary endpoint was overall response rate (ORR; ≥50% PSA decline or radiographic response). Results: Of 73 randomized patients, 65 received protocol treatment: 34 on Arm A (26 docetaxel+carboplatin; 8 carboplatin alone) and 31 on Arm B. Thirteen patients (38%) in Arm A and 20 (65%) in Arm B had ≥Grade 3 treatment-related adverse events (TrAEs). ORR was 15% in Arm A (5/34; 5/26[19%] with docetaxel+carboplatin) and 0% in Arm B (0/31). At interim analysis after 65 of planned 130 patients were treated, enrollment was halted due to futility. Homologous recombination repair deficiency status from tissue and blood did not correlate with clinical outcomes, but ATM-deficiency or high levels of phoshpo-KAP1 detected in tissue was associated with clinical benefit across both arms of the trial. Conclusions: Berzosertib+carboplatin demonstrated lower ORR and more frequent ≥grade 3 TrAEs compared to docetaxel+carboplatin in this heavily pre-treated, biomarker-unselected population. NCT03517969

11526 Background: There are no FDA-approved treatments for advanced cCS. Chemotherapy provides limited benefit. IDH1/2 mutations (m) occur in 50% of cCS. Both IDHm and wild-type cCS harbor epigenetic dysregulation. In preclinical models, HDAC + DNMT inhibition (i) suppressed growth by inducing apoptosis, reversing the hypermethylated state, and upregulating expression of interferon (IFN) response genes including PDL1(1). This prompted a phase 2 study of HDACi + DNMTi in cCS, which failed to meet the 1° endpoint of ORR. The majority of pts had a best response of stable disease, with a trend towards improved mPFS in IDHm (2). Here we report correlative analysis of NCI 10330. Methods: NCI 10330 is a single-arm, multicenter, phase 2 study of belinostat with SGI-110 or ASTX727 in advanced cCS. All pts were required to have pre- and on-treatment (tx) biopsies (Cycle 2, Day 3-5). Tissue was evaluated with whole exome sequencing (WES) and RNA sequencing (RNAseq). From RNAseq, Tumor Inflammation Signature Scores (TISS) and Tumor Microenvironment functional Gene Set Enrichment Analysis scores (TME GSEA) were calculated as the mean of the log2 normalized counts of 18 signature genes (Danaher et al. J Imm Can 2018) and pre-defined gene sets (3), respectively. Wilcoxon rank sum test was used to analyze TME GSEA between pre- and on-tx samples. Differential expression was significant if |FC| > 1.33, adjusted P <0.01. Results: 19 pts were treated; all received paired biopsies. WES was adequate in 7/19 (37%) pts, with IDHm identified in 3/7 (43%) pts. All pts were MSI-stable, TMB: 1.01-3.57 mut/Mb. RNAseq was adequate in 7/19 (37%) pts at pre-tx and 5/19 (26%) pts at on-tx. TISS ranges trended higher for pre-tx (8.77-10.14) vs on-tx (7.36-9.51) samples. TME GSEA identified significantly enriched tumor immune infiltration (p < 0.05) in pre- vs on-tx samples. Differential analysis identified several gene sets related to inflammation overexpressed in pre-tx samples only, including IFN response. On-tx samples were enriched in myogenesis and coagulation gene sets. Conclusions: This is the first study to describe transcriptomic changes following epigenetic tx in cCS. Contradictory to our preclinical data, HDACi + DNTMi resulted in low expression of inflammation. Prior studies reported that the immune infiltrate of CS at progression is immunosuppressive; higher immune infiltrate is correlated with worse outcomes (4). Loss of inflammation may have implications for disease stability experienced by most pts on NCI 10330. Further analyses are planned to correlate TME (pro- vs anti-inflammatory infiltrates) and outcomes. Analyses are limited by small sample size, highlighting the challenges in collecting adequate CS specimens. 1. Sheikh, Schwartz et al. Mol Cancer Ther 2021. 2. Lacuna et al. ASCO 2023: #11531. 3. Bagaev et al. Can Cell 2021. 4. Richert et al. J Bone Onc 2020. Clinical trial information: NCT04340843 .

PURPOSE Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth. PATIENTS AND METHODS NCI Protocol 10250 is a single-arm, open-label, multicenter, phase II study evaluating olaparib and temozolomide in advanced uLMS. Patients with progression on ≥1 prior line received temozolomide 75 mg/m2 orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles. The primary end point was the best objective response rate (ORR) within 6 months. A one-stage binomial design was used. If ≥5 of 22 responded, the treatment would be considered promising (93% power; α = .06). All patients underwent paired biopsies that were evaluated with whole-exome sequencing (WES)/RNAseq and a RAD51 foci formation assay. RESULTS Twenty-two patients were evaluable. The median age was 55 years, and 59% had received three or more prior lines. Best ORR within 6 months was 23% (5 of 22). The overall ORR was 27% (6 of 22). The median progression-free survival (mPFS) was 6.9 months (95% CI, 5.4 months to not estimable). Hematologic toxicity was common (grade 3/4 neutropenia: 75%; thrombocytopenia: 32%) but manageable with dose modification. Five of 16 (31%) of tumors contained a deleterious homologous recombination gene alteration by WES, and 9 of 18 (50%) were homologous recombination-deficient by the RAD51 assay. In an exploratory analysis, mPFS was prolonged for patients with homologous recombination-deficient versus homologous recombination-proficient tumors (11.2 v 5.4 months, P = .05) by RAD51. CONCLUSION Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.

PURPOSE Polycythemia vera (PV) is characterized by JAK/STAT activation, thrombotic/hemorrhagic events, systemic symptoms, and disease transformation. In high-risk PV, ruxolitinib controls blood counts and improves symptoms. PATIENTS AND METHODS MAJIC-PV is a randomized phase II trial of ruxolitinib versus best available therapy (BAT) in patients resistant/intolerant to hydroxycarbamide (HC-INT/RES). Primary outcome was complete response (CR) within 1 year. Secondary outcomes included duration of response, event-free survival (EFS), symptom, and molecular response. RESULTS One hundred eighty patients were randomly assigned. CR was achieved in 40 (43%) patients on ruxolitinib versus 23 (26%) on BAT (odds ratio, 2.12; 90% CI, 1.25 to 3.60; P = .02). Duration of CR was superior for ruxolitinib (hazard ratio [HR], 0.38; 95% CI, 0.24 to 0.61; P < .001). Symptom responses were better with ruxolitinib and durable. EFS (major thrombosis, hemorrhage, transformation, and death) was superior for patients attaining CR within 1 year (HR, 0.41; 95% CI, 0.21 to 0.78; P = .01); and those on ruxolitinib (HR, 0.58; 95% CI, 0.35 to 0.94; P = .03). Serial analysis of JAK2V617F variant allele fraction revealed molecular response was more frequent with ruxolitinib and was associated with improved outcomes (progression-free survival [PFS] P = .001, EFS P = .001, overall survival P = .01) and clearance of JAK2V617F stem/progenitor cells. ASXL1 mutations predicted for adverse EFS (HR, 3.02; 95% CI, 1.47 to 6.17; P = .003). The safety profile of ruxolitinib was as previously reported. CONCLUSION The MAJIC-PV study demonstrates ruxolitinib treatment benefits HC-INT/RES PV patients with superior CR, and EFS as well as molecular response; importantly also demonstrating for the first time, to our knowledge, that molecular response is linked to EFS, PFS, and OS.

Abstract Philadelphia-negative Myeloproliferative Neoplasms (MPN), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), Myelofibrosis (Primary [PMF] and secondary to PV and ET [PPV-, PET-MF] and unclassified MPN (U-MPN), are associated with an increased risk of venous thrombosis in unusual sites, such as splanchnic vessels (SVT). SVT can lead to complications such as portal hypertension, esophageal and gastric varices, ascites,hepatic failure and biliopathy. According to a meta-analysis MPN is the underlying cause of portal vein thrombosis (PVT) in 31.5% and Budd Chiari syndrome (BCS) in 40.9% of cases (Smalberg, 2012); a more in-depth analysis of clinical characteristics and evolution of MPN-associated SVT has been hampered by heterogeneity of cohorts comprising small number of cases. We conducted a retrospective multicenter study in patients (pts) with SVT associated with WHO2008-diagnosed MPN, with the aim to describe patient characteristics, disease course and prognostic factors with potential implications for clinical practice. Data were collected from 16 international hematologic centers in the framework of the Italian AGIMM and the IWG-MRT groups. We collected 519 cases of pts with PVT, splenic or mesenteric vein thrombosis (75.1%) and BCS (24.9%) associated with MPN. We used as comparator a cohort of 1686 controls (Ctr) represented by MPN without (w/o) SVT: 741 ET (43.9%), 684 PV (39.7%), 261 PMF (15.5%). Frequency of MPN associated with SVT was 37.8% ET (n=196), 36.8% PV (n=191), 15.4% MF (n=80), 10% U-MPN (n=52). Median follow-up was 89.9 months (mo) (range 0.5-430). For SVT vs Ctr group females were 54.5% vs 44.4% in PV (P=0.001), 68.4 vs 63.5% (p=0.13) in ET, 63.7% vs 29.1% in PMF (p<0.0001); median age at MPN diagnosis (dg) was 43.5 yr (range 12-90) vs 60.6 yr (range 12-93) (p<0.0001). Age at SVT dg was 44 yr (range 15-85). In 240 cases (46.7%) MPN and SVT dg were coincident, in 121 (23.6%) SVT occurred before MPN dg (median 26 mo, range 4-307) and in 153 (29.8%) during MPN follow up (median 68 mo, range 4-362). JAK2V617F mutation was found in 94% PV vs 94% in Ctr, 84% vs 61% ET (p<0.0001), 88.1% vs 68% PMF (p=0.006) and in 93% U-MPN. Erythropoietin-independent colonies (EEC) were evaluated in 111 SVT pts and found in 80 (72%), accounting for 38/48 PV (79%), 31/44 ET (70.5%), 9/12 PMF (75%) and 2/7 U-MPN (28.6%). At dg, SVT PV pts had lower hemoglobin levels than Ctr: median was 17.4 g/dL vs 18.5 g/dL (p<0.0001) in male, 16.9 g/dL vs 17.7 g/dL (p=0.0006) in female. A co-existing thrombophilic status was found in 38.5% SVT vs 11.8% of Ctr (p<0.0001). Recurrent SVT occurred in 12.2% of pts with a rate of 1.6% person/year (CI 1.2-2.1); risk of venous thrombosis other than SVT was increased in SVT group vs Ctr (p=0.02), with no difference for arterial thrombosis. Hemorrhage was more frequent in SVT group (32%) vs Ctr (7.2%)(p<0.0001), mainly related to esophageal varices, which were present in 66.9% of SVT pts. There was no difference in evolution to MF and acute leukemia (AL) for PV and ET pts with and w/o SVT, while risk of AL was lower in MF with SVT (p<0.00001). Overall survival was shorter in ET pts with SVT vs Ctr (p<0.0001). In PMF survival was better in SVT group (p<0.00001) and was associated with a higher proportion of SVT pts in lowest risk categories: IPSS low 65%, intermediate-1 20%, intermediate-2 10% and high 5% compared with 15%, 34%, 25% and 26% in Ctr group. At last FU, 79/519 pts (15.2%) had died; causes of death were evolution to AL (15.4%), other cancers (13.8%), disease progression without AL (10.8%), SVT (10.8%), hepatic failure and venous thrombosis other than SVT (7.7% each), heart failure and arterial thrombosis (6.2% each), hemorrhage (5.5%), renal failure and infection (4.6% each). Therapy after SVT included anticoagulation in 77%, antiaggregant in 21.2% and combination in 1.8%; 70% received cytotoxic drugs; 12.4% were treated with transjugular porto-systemic shunt. Beta blocker therapy was used in 48.5% of pts and correlated with improved survival (p=0.041) MPN associated with SVT correlated with younger age and female sex and might antedate the clinical phenotype in a quarter of the patients. MPN-associated SVT equally affected PV and ET, was more likely to occur in the presence of JAK2V617F or underlying thrombophilia and predicted recurrent venous but not arterial thrombosis. The apparent association of SVT with better or worse prognosis in PMF and ET, respectively, requires further investigation. Disclosures No relevant conflicts of interest to declare.

Abstract Philadelphia-negative Myeloproliferative Neoplasms (MPN) include Polycythemia Vera (PV), Essential Thrombocythemia (ET) and Myelofibrosis Primary (PMF) and secondary to PV and ET (PPV-, PET-MF); included are also some less characterized entities defined as unclassified MPN (U-MPN). Risk of arterial and venous thrombosis is increased in MPN patients, and thrombosis is one of most important causes of mortality and morbidity. The risk of venous thrombosis in unusual sites, such as splanchnic vessels (SVT), is particularly associated with MPN; SVT can lead to complications such as portal hypertension, esophageal and gastric varices, ascites and hepatic failure. A recent meta-analysis reported that a MPN is the underlying cause of portal vein thrombosis in 31.5% and of Budd Chiari syndrome in 40.9% of cases (Smalberg, 2012). A significant association of SVT with JAK2V617F mutated MPN was reported (Dentali, 2009) but study of other correlations has been hampered by heterogeneity of available patient cohorts comprising relatively small number of cases. We conducted a retrospective multicenter study collecting clinical and biological data of patients (pts) with SVT associated with MPN diagnosed according to WHO2008 criteria, aiming to describe patients’ characteristics, trends and prognostic factors, and their potential implications for clinical practice. Data were collected from 15 international hematology centers in the framework of IWG-MRT. We collected 475 cases of pts with portal, splenic or mesenteric vein thrombosis (75.2%) or Budd Chiari syndrome (24.8%) associated with MPN. In 32% of cases, simultaneous involvement of portal (69.1% of total thrombosis), splenic (30.5%) and mesenteric (25.3%) veins occurred, and in 1.7% they were associated with Budd Chiari syndrome. Frequency of MPN subtype: 38.1% ET (n=181), 34.9% PV (n=166), 16.2% MF (n=77), 10.8% U-MPN (n=51). Median follow-up 87.9 mo (range 0.5-430); female 61.3% (n=292; P<0.0001 vs male); median age at MPN diagnosis (dg) 44.4 y (range 12-90), at SVT dg 44.9 y (range 17-85). In 229 cases (48%) MPN and SVT dg were coincident, while in 104 (22%) SVT occurred before MPN dg (median 40 mo, range 5-335) and in 129 (27%) during MPN follow up (median 79 mo, range 5-394). JAK2V617F mutational status is available for 361 pts: 99% PV, 84.7% ET, 88.1% PMF and 92.9% U-MPN pts were JAK2V617F positive, with a mean allele burden of 56±27.4%, 33.1±25.5%, 39.3±19.4% and 23.8±11.9%, respectively. Erythropoietin-independent colonies (EEC) were present at diagnosis in 80/110 evaluated cases (72.7%), 38/47 PV (84.4%), 32/45 ET (71.1%), 8/11 PMF (72.7%) and 2/7 U-MPN (28.6%). A concurrent thrombophilic state was found in 38.9% of cases. A 12.3% of pts experienced a recurrence of SVT after a median of 29 mo (range 1-378.3) and 35.8% developed thrombosis in other sites (17.7% arterial, 19.3% venous). Esophageal varices were found in 70.6% from which 31.9% bled. MF transformation occurred in 32/166 PV (19%) and in 23/181 ET (13%) pts, with median time to progression of 122.3 mo (range 5.4-377.3) and 125.1 mo (range 39.3-255.3), respectively. Evolution to acute leukemia (AL) occurred in 12 pts (2.7%), of which 2 PMF, 6 PV and 4 ET. In 3 PV and 1 ET pts a PPV and PET-MF transformation occurred before AL. After SVT, 77% of pts received anticoagulation, 23.5% antiaggregant therapy and 1.5% both; 68.8% received cytotoxic drugs, 11.4% of pts were treated with trans jugular porto-systemic shunt. No differences in survival were noted with these approaches. Beta blocker therapy was used in 48.5% of pts and correlated with improved survival (p=0.041) At last follow up 70/473 pts (14.8%) died; causes of death are evolution to AL (16.4%), other cancers (14.5%), disease progression without AL (12.7%), SVT (10.9%), hepatic failure and venous thrombosis other than SVT (9.1% each), heart failure and arterial thrombosis (7.3% each), hemorrhage (5.5%), renal failure and infection (3.6% each). After 10 y follow up 8/166 PV (5%), 14/181 ET (8%), 14/77 PMF (18%) and 1/51 U-MPN (1.96%) pts died (p<0.01). Survival was significantly affected by occurrence of thrombosis other than SVT (p<0.0001) but not recurrence in splanchnic vessels (p=0.068). This large study confirms the strong association between JAK2V617F-mutated MPN and SVT and identifies the category of U-MPN as the prognostically more favorable; thrombosis at sites outside the splanchnic vasculature remains the leading cause of death. Disclosures: No relevant conflicts of interest to declare.

Abstract MAJIC is a phase II trial of Ruxolitinib (RUX) vs Best Available Therapy (BAT) in essential thrombocythemia (ET) patients with resistance/intolerance to Hydroxycarbamide (HC) per European LeukemiaNet (ELN) criteria. Primary outcome was rate of complete hematological response (CHR) within 1 year (ELN criteria); secondary outcomes included partial HR, safety, thrombosis, hemorrhage, progression free survival (including transformation), molecular response (MR), symptom & quality of life (QOL) assessment. We present new data concerning molecular, symptom & clinical responses. Patients were stratified by JAK2V617F status, patient-reported symptoms & QOL determined using EQ5D, MDASI & MPN Symptom Assessment Form (MPN10), & compared using linear mixed models of post-baseline scores through month 12 adjusting for baseline; response was defined as ≥50% reduction in MPN10 total symptom score (TSS). JAK2/CALR/MPL allele burdens were assessed at baseline & 4 monthly. 110 patients were eligible for the modified ITT analysis, 58 (52%) & 52 (48%) in RUX & BAT arms respectively, comprising 44 males, 66 females, mean age 64.2ys, & resistant (24.5%), intolerant (51.8%) or both (22.7%) to HC. CHR was achieved in 27 (46.6%) of RUX patients vs 23 (44.2%) BAT patients (χ2 test p= 0.81). PHR occurred in 26 (44.8%) & 27 (51.9%) of RUX & BAT treated respectively. Grade 3 or 4 anemia occurred in 19% & 0% for RUX arm vs 0% (both grades) for BAT arm, grade 3 or 4 thrombocytopenia in 5.2% & 1.7% of RUX vs 0% (both grades) of BAT patients respectively. Grade 3 or 4 infections occurred in 10.3% of RUX patients vs 3.6% BAT arm. 9 RUX treated patients had 10 thrombotic events & 1 RUX patient a hemorrhage; vs 5 thrombotic & 5 hemorrhagic events in BAT patients (adjusted following central review). Transformations to post-ET MF occurred in 8 RUX vs 3 BAT treated patients, 1 RUX patient developed AML. 2 non-treatment related deaths occurred in each arm. Mean MPN-10 TSS & individual symptoms of early satiety & itching during the first 12 months were all significantly lower for RUX vs BAT (all p<0.05). Patients who achieved CHR had significantly better TSS, fatigue, inactivity, concentration problems, & MDASI symptom interference (all p<0.05) at baseline vs those without; however, scores during treatment did not appear to differ between CHR & non CHR groups after adjusting for these baseline differences. Allele burden during study & MRs (per ELN-IWG criteria Barosi Blood 2013) are shown in Table 1. Assays for JAK2 V617F were performed independently in 3 centres using qPCR (Guy's), TSCA NGS (Oxford) & amplicon-based NGS (Salisbury) & revealed Mean (range): JAK2 (Guy's): 33.2 (0.1-94.6), N=52; JAK2 (Oxford): 38.0 (0.5-92.2), N=52; JAK2 (Sal): 38.3 (0-90.0), N=50 (limited to JAK2 positive only). With Interclass Correlation Coefficient as follows ICC (Guy's v Oxford): 0.92 (95% CI 0.86-0.95) ICC (Guy's v Sal): 0.92 (95% CI 0.86-0.95) ICC (Oxford v Sal): 0.997 (95% CI 0.994-0.998). Notably MRs (n=5) only occurred with RUX treatment. There was no pattern of MR or progression with C/PHR or transformation, but 1 patient who transformed to PET MF had a complete MR. In a separate analysis baseline symptoms & QOL were not associated with JAK2, CALR, nor MPL status. Within RUX, baseline symptoms & QOL did not predict MR; however, fatigue, early satiety & abdominal discomfort (all p<0.05, Table 1) were significantly lower among those with MR vs not during treatment with a descriptively higher symptom response rate (2/4 [50%] vs 9/30 [30%]). Three non pre-specified multivariate analyses were performed to assess baseline factors influencing CHR (modelled for: treatment received, HC resistance or intolerance, white cell count, platelets, Hb & JAK2/CALR status); occurrence of ≥ grade 3 anemia or thrombocytopenia (modelled for: Hb (≥ 100g/dl) JAK2/CALR status); & transformation to PET-MF (modelled for: treatment, Hb ≤100g/dl). Only baseline Hb ≤100g/dl was significant for grade 3+ anemia (OR [95% CI]=0.17 [0.04, 0.72]), & PET-MF only occurred in patients with baseline WBC <10x109/L. This updated analysis shows that HC resistant/intolerant ET is clinically & molecularly diverse. We confirm that these patients are at high risk of thrombosis & transformation as suggested in prior retrospective studies. Molecular responses were limited to RUX & for the first time we demonstrate such responses may correlate with symptom improvement but not always with progression events. Disclosures Harrison: Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Aliman:Novartis: Other: Institutional funding and grant for international conference. . Chen:Novartis: Other: Advisory Board. Coppell:Novartis: Other: Travel, accommodation and conference attendance. Knapper:ONO pharmaceuticals: Research Funding; Novartis: Honoraria, Other: Travel and expenses for international conferences. Ali:Novartis: Honoraria, Other: Conference sponsorship, advisory board meetings. Hamblin:Novartis: Other: Advisory Board. Dueck:Bayer: Honoraria. Cross:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Mesa:Celgene: Research Funding; Promedior: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. McMullin:Novartis: Honoraria, Speakers Bureau.

Key Points After hydroxycarbamide therapy in high-risk ET, ruxolitinib showed no improvement for complete or partial response rates compared with BAT. Ruxolitinib significantly improved some disease-related symptoms, but rates of thrombosis, hemorrhage, or transformation were not different.