Rezasoltani, Mahsa

Abstract The comparative value of liposomal cytarabine/daunorubicin (CPX-351) versus venetoclax plus a hypomethylating agent (Ven-HMA) in the frontline treatment of older adults with primary ( de novo ) or secondary acute myeloid leukemia (AML) remains uncertain. In the current study, we retrospectively examined outcomes of 600 patients with newly diagnosed AML treated with CPX-351 (N = 112) or Ven-HMA (N = 488). AML subtypes included de novo (46%), post-myelodysplastic syndrome (MDS) (19%), post-myeloproliferative neoplasm (MPN) (12%), post-MDS/MPN (6%), therapy-related (17%) and AML with myelodysplasia-related genetic abnormalities (AML-MR; 46%). Patients receiving CPX-351 were younger (median 65 vs. 73 years; p < 0.01), predominantly female (50% vs. 38%; p = 0.02), more likely to have secondary AML (68% vs. 51%; p < 0.01), and less likely to harbor NPM1 MUT (5% vs. 12%; p = 0.02). Rates of complete response with or without count recovery (CR/CRi) were comparable between CPX-351 and Ven-HMA (55% vs. 60%; p = 0.30), including in AML-MR (60% vs. 63%; p = 0.70). Ven-HMA use was associated with fewer infectious complications (62% vs. 83%; p < 0.01) and yielded higher CR/CRi rates in males (60% vs. 45%; p = 0.04), de novo AML (68% vs. 50%; p = 0.03), and in the presence of STAG2 MUT (86% vs. 44%; p = 0.02), or CEBPA MUT (88% vs. 50%; p = 0.03). Overall survival censored for transplant, was similar (median 10 vs. 13 months; p = 0.90), with Ven-HMA being superior in post-MDS AML (median 12 vs. 7 months; p = 0.02) and CPX-351 in the presence of SF3B1 MUT (not reached vs. 14 months; p < 0.01). Our findings suggest that Ven-HMA is as effective and less toxic than CPX-351 in newly diagnosed AML, including AML-MR, despite selection of younger, fitter patients for CPX-351.

Abstract Introduction Management of acute leukemia (AL) during pregnancy remains challenging. In the first trimester, chemotherapy is toxic to the fetus, while delaying treatment may endanger maternal health, often prompting recommendations for pregnancy termination. In later trimesters, although the risk of congenital malformations decreases, complications such as preterm labor remain prevalent. Delivery prior to chemotherapy may be considered in advanced gestation. This study aimed to describe maternal and fetal outcomes of patients diagnosed with AL during pregnancy. Methods Following institutional review board approval, we retrospectively identified pregnant patients diagnosed with AL between 1995 and 2025 across Mayo Clinic sites (Minnesota, Arizona, Florida). We recorded leukemia subtype, treatment course, maternal and fetal outcomes. Results We identified 18 patients diagnosed with AL during pregnancy, including 11 with acute myeloid leukemia (AML) and 7 with acute lymphoblastic leukemia (ALL). Ten were diagnosed in the first trimester, 3 in the second, and 5 in the third. In the AML group (n=11; median age 30 years, range 18-42), one patient had acute promyelocytic leukemia (APL). ELN 2022 risk stratification was favorable in 5 (45%), intermediate in 4 (36%), and adverse in 2 (18%). In the ALL group (n=7; median age 23 years, range 19-34), 5 had B-ALL (one Philadelphia chromosome-positive) and 2 had T-ALL. All ALL cases were diagnosed in the first trimester. Among first-trimester AMLs, 2 of 3 had core-binding factor (CBF) AML. All eight patients diagnosed in the second and third trimesters had AML (1 APL, 2 CBF AML, 1 KMT2A-rearranged, 1 with DEK::NUP214 fusion, 1 complex karyotype including t(8;21), 2 with normal karyotype). Overall, 15 (83%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi) after initial induction. One patient had refractory disease and achieved partial remission after salvage, another had refractory disease and achieved CR after multiple lines of therapy, and a third achieved CR after FLAG-idarubicin and revumenib. Five patients received chemotherapy during pregnancy (3 in the first trimester, 1 in the second, 1 in the third); two of these resulted in live births. Among the 10 patients diagnosed in the first trimester, all underwent therapeutic or spontaneous abortion. Of the 3 second-trimester diagnoses, 2 underwent spontaneous or therapeutic abortion at 15 weeks. The third received 7+3 induction at 24 weeks for KMT2A-rearranged AML, followed by preterm delivery at 26 weeks and re-induction with FLAG-idarubicin plus revumenib, achieving CR. Among the 5 third trimester diagnoses, 4 delivered preterm infants (median gestational age 33 weeks) prior to chemotherapy. One patient received 7+3 at 29 weeks and delivered a viable preterm infant at 36 weeks. At a median follow-up of 6.5 years, 5 of 11 patients with AML (45%) and 3 of 7 patients with ALL (43%) died, mostly due to disease progression. Median overall survival was not reached in either group. Causes of death were as follows: 1 of AML, 1 of ALL, 3 of acute stem cell transplant (SCT) complications, 1 of chronic SCT complications, 1 of Hodgkin lymphoma, and 1 of pneumonia. Among patients diagnosed in the second and third trimesters (n=8, all with AML), 6 (75%) resulted in live births: 5 of 5 (100%) third-trimester diagnoses and 1 of 3 (33%) second-trimester diagnoses. All received intensive induction: 7+3 (n=5), 7+3 + ATRA (n=1), 7+3 + gilteritinib (n=1), and 7+3 + nilotinib (n=1). Of the second-trimester group, only one received induction prior to delivery; she later achieved CR with FLAG-ida and revumenib. Among the third-trimester group, one patient received chemotherapy prior to delivery and achieved CR followed by SCT. All but one of the 8 AML patients achieved CR after initial therapy. Conclusions Successful pregnancy outcomes were achieved in 75% of patients diagnosed with AML during the late second or third trimester. Notably, 5 (28%) of patients received chemotherapy during pregnancy. Larger, multi-institutional cohorts are warranted to further characterize the incidence and outcomes of AL in pregnancy.

Abstract Venetoclax (Ven) in combination with hypomethylating agents (HMA) is widely used as frontline treatment in older or unfit patients with acute myeloid leukemia (AML). Liposomal cytarabine and daunorubicin (CPX-351) is FDA-approved for the treatment of secondary AML, including therapy-related (t-AML) and AML with myelodysplasia-related changes (AML-MR). The current study aimed to provide a comprehensive comparison between the two treatment strategies to better inform clinical decisions. Methods The current retrospective analysis was performed under an institutional review board approved minimal risk protocol at Mayo Clinic (MN, AZ, FL). AML-MR gene mutations or cytogenetic abnormalities were categorized according to the International Consensus Classification (Arber et al. Blood 2022;140:1200). Treatment response was assessed according to the 2022 European LeukemiaNet (ELN) criteria (Dohner et al. Blood 2022;140:1345). Overall survival (OS) analysis was censored for allogeneic stem cell transplant (ASCT). Statistical analyses were performed using JMP Pro (Version 18.0.0). Results A total of 600 patients with newly diagnosed AML (ND-AML) treated with CPX-351 (N-112, 19%), or Ven-HMA (N=488, 81%) were included. AML subtypes included de novo (N=277, 46%), post-myelodysplastic syndrome (post-MDS, N=114,19%), post-myeloproliferative neoplasm (post-MPN, N=70, 12%), post-MDS/MPN (N=36, 6%), t-AML (N=103, 17%) and AML-MR (N=274, 46%). Compared with those treated with Ven-HMA, patients receiving CPX-351 were younger (median age 65 vs 73 years; p&lt;0.01), more likely to be female (50% vs 38%; p=0.02), more frequently diagnosed withsecondaryAML (68% vs 51%; p&lt;0.01), and less likely to have NPM1MUT (5% vs 12%; p=0.02) whereas ELN 2022 cytogenetic risk distribution was similar between the two (adverse risk; 43% vs 40%; p=0.5). Comparison of treatment response and survival Complete response rates with (CR) or without (CRi) count recovery were similar between CPX-351 and Ven-HMA overall (55% vs 60%) as well as specifically in patients with AML-MR (60% vs 63%), adverse karyotype (44% vs 44%), NPM1MUT (100% vs 89%), TP53MUT(32% vs 45%), IDH1MUT (60% vs 76%), IDH2MUT (63% vs 77%), SF3B1MUT(71% vs 45%), and CBLMUT (33% vs 69%) [p&gt;0.05 in all instances]. Compared to those with CPX-351, CR/CRi rates with Ven-HMA were superior in males (60% vs. 45%; p=0.04) and in patients with de novo AML (68% vs. 50%; p=0.03), STAG2MUT (86% vs. 44%; p=0.02), or CEBPAMUT (88% vs. 50%; p=0.03); infectious complications were significantly more frequent with CPX-351 (83% vs 62%, p&lt;0.01). At a median follow-up of 12 months (range; 1-88), 416 (69%) deaths, 179 relapses (44% in CPX-351 and 52% in Ven-HMA responders) and 149 ASCTs (53% in CPX-351 and 18% in Ven-HMA) were documented. OS rates were similar between CPX-351 and Ven-HMA, in general (median 10 vs 13 months), as well as in patients with adverse karyotype, TP53MUT, IDH1MUT, and IDH2MUT (p&gt;0.05 in all instances). By contrast, OS was superior in Ven-HMA-treated patients with post-MDS AML (median 12 vs. 7 months; age-adjusted p=0.02) and in CPX-351-treated patients harboring SF3B1MUT(median not reached vs 14 months; age-adjusted p&lt;0.01). In addition, a borderline-significant OS advantage for CPX-351 was apparent in patients with PTPN11MUT (13.5 vs 8 months; p=0.08). Comparison in ICC defined AML-myelodysplasia-related CR/CRi and OS rates were comparable between patients treated with CPX-351 (N=57) or Ven-HMA (N=217), with response rates of 60% vs 63% (p=0.68) and median OS of 10 vs 14 months (p=0.61), respectively. However, OS was superior with Ven-HMA in patients with post-MDS AML (15 vs 8 months; age-adjusted p=0.02) and with CPX-351 in those with SF3B1MUT (NR vs 14 months; age-adjusted p=0.02). Conclusions: The current study suggests that Ven-HMA was as effective and possibly less toxic than CPX-351 for the treatment of ND-AML, including AML-MR, despite the bias for younger and fitter patients treated with the latter regimen. Observed differences involving patients with SF3B1MUT or post-MDS AML require validation in prospective studies and provide parameters for developing treatment-specific predictive models that will be presented at the meeting.

Abstract Background: JAK2-unmutated erythrocytosis constitutes a spectrum of hereditary and acquired entities. We assessed the diagnostic yield and utility of next generation sequencing panel for hereditary erythrocytosis (NGS-HEP) in adults with JAK2-unmutated and otherwise unexplained erythrocytosis (OUE). Additionally, we describe the clinical phenotype, genetic findings, treatment approaches, and thrombotic outcomes in this cohort. Methods: Adults (≥18 years) withOUE, defined as hemoglobin (Hgb) &gt;16.5 g/dL or hematocrit (Hct) &gt;49% in males and Hgb &gt;16 g/dL or Hct &gt; 48% in females, negative for JAK2 exon 12-15mutations, absence of acquired cause, and high-oxygen affinity variants, underwent NGS-HEP; the gene panel included ACO1, ANKRD26, BHLHE41, BPGM, CYB5A, CYB5R3, EGLN1, EGLN2, EGLN3, EPAS1, EPO, EPOR, GFI1B, HIF1A, HIF1AN, HIF3A, JAK2, KDM6A, PFKM, PIEZO1, PKLR, SH2B3, SOCS3 and VHL, including deletion/duplication analysis.Variant curation was performed using ACMG-AMP guidelines and classified as pathogenic or variants of uncertain significance (VUS). Family and thrombosis history, and symptoms were recorded. Results: A total of 44 adult patients with JAK2-unmutated OUE (median age 48 years, range 21–79; 34 males [77%]) underwent NGS-HEP at the Mayo Clinic between March 2023 and June 2025. Variants were identified in 27 patients (61%), with a single variant detected in 19 (70%) and two distinct variants in 8 (30%). 26 variants (96%) were classified as heterozygous VUS and involved PIEZO1 (n=9, 20%; median variant allele frequency [VAF] 47.1%), HIF1A (n=8, 18%;46.2%), ANKRD26 (n=4, 9%;43.7%), SH2B3 (n=3, 7%; 49.9%), HIF3A (n=3, 7%;51.4%), EGLN2 (n=2, 5%;47.9%), BPGM (n=1, 2%; 50.4%), VHL (n=1, 2%; 41.8%), EPO (n=1, 2%; 45.4%) and BHLHE41 (n=1, 2%; 54.2%), while a pathogenic mutation in PKLR was detected in one patient. Presenting median Hgb/Hct values for males and females, respectively were 18.3 g/dL/53.5% and 16.9 g/dl/51.2% in variant- positive cases, and 17.8 g/dl/53.1% and 16.1 g/dl/49.3% in variant-negative cases (p&gt;0.05). Median serum erythropoietin (sEpo) levels were 8.35 mIU/mL (range: &lt;1-52.9) vs 8.8 mIU/mL (range: 1.6-54.7), respectively (p=0.67). Notably, sEpo was &lt; 1 mIU/mL in a patient with ANKRD26/HIF3A VUS. Family history of erythrocytosis was documented in 5 patients (11%). Hyperviscosity-related symptoms were reported in 24 patients (55%), with no significant difference in prevalence between variant-positive and variant-negative cases (59% vs 47% p=0.42). Also, there was no significant association between the presence of symptoms and Hgb or Hct levels (p&gt;0.05). Eight thrombotic events occurred in 7 patients (16%; median age 44 years; 71% males; 4 arterial and 4 venous; 3 provoked deep venous thromboses). Five (71%) of the 7 patients harbored VUS in PIEZO1, PIEZO1/HIF1A, ANKRD26, SH2B3, or BHLHE41. Notably, two younger male patients experienced arterial events in the absence of identifiable risk factors: a 32-year-old with PIEZO1/HIF1A VUS (VAF 46.2%/47.6%; sEpo 10.3 mIU/mL) suffered a myocardial infarction, and a 35-year-old with SH2B3 VUS (VAF 50.2%; sEpo 3.7 mIU/mL) had recurrent cerebrovascular accident despite phlebotomy, aspirin and apixaban. Overall, there was no significant association between thrombosis and the presence of a variant (19% in variant-positive vs 12% in variant-negative, p=0.54). Active therapies included phlebotomy in 22 patients (50%), antiplatelet agents in 23 (52%), systemic anticoagulation in 5 (11%), and hydroxyurea in one patient (2%). Among those who received phlebotomy, 10 patients (45%) reported improvement in symptoms, however, symptom relief did not correlate with Hgb or Hct levels (p&gt;0.05). A separate analysis of 9 patients with heterozygous PIEZO1 VUS, none of whom had undergone splenectomy, showed a numerically higher incidence of symptoms (67% vs 51%) and thrombosis (22% vs 14%) compared to those without PEIZO1 variants, although the differences were not statistically significant (p&gt;0.05). Conclusion: NGS-HEP yielded a molecular diagnosis in 61% of adults with JAK2-unmutated and OUE with heterozygous PIEZO1 variants being the most frequent. No consistent association was observed between variant status and presence of hyperviscosity-related symptoms or thrombotic events. These findings underscore the importance of NGS-HEP testing in the diagnostic workup of JAK2-unmutated and OUE and continued investigation into novel candidate genes.

Introduction: Resistant and uncontrolled hypertension pose persistent clinical and public health challenges. Renal denervation, a catheter-based procedure targeting renal sympathetic nerves, has emerged as a promising approach to lower blood pressure by reducing sympathetic overactivity. Hypothesis: A systematic review and meta-analysis of sham-controlled trials investigated whether renal denervation results in sustained blood pressure reduction across short-, medium-, and long-term follow-up. Methods: We searched PubMed, Embase, CENTRAL, and Web of Science through March 2025. The protocol was registered in PROSPERO (CRD420251015937). Randomized, sham-controlled trials of renal denervation in resistant/uncontrolled hypertension were included. Primary outcomes were ambulatory blood pressure (daytime, nighttime, and 24-hour); secondary outcomes included office and home blood pressure measurements. Follow-up durations were categorized into three groups: less than 6 months, 6–12 months, and greater than 12 months. Risk of bias was assessed using RoB-2. Results: Twenty trials (25 reports) with 2,167 RDN patients and 1,744 sham controls were included. Most trials had a low risk of bias. RDN significantly reduced 24-hour SBP (–3.29 mmHg, 95% CI: –5.91 to –0.67) and DBP (–1.42 mmHg, 95% CI: –2.29 to –0.55), despite high heterogeneity (I2 > 90%). Daytime DBP showed a significant reduction (–2.90 mmHg, 95% CI: –4.39 to –1.41), while other BP measures were less consistent. Home SBP was significantly reduced (–5.04 mmHg, 95% CI: –8.50 to –1.58). At 6–12 months, 24-hour SBP reduction persisted (–3.36 mmHg, 95% CI: –5.71 to –1.01), but DBP effects were nonsignificant. Long-term follow-up revealed nonsignificant changes in systolic blood pressure and diastolic blood pressure. Conclusions: Renal denervation modestly lowers BP in the short term (<6 months). Mid-term SBP reduction persists, but diastolic and long-term effects are inconsistent. These findings highlight the need for refined patient selection, optimized techniques, and longer follow-up trials.

We sought to develop a survival model in chronic myelomonocytic leukemia (CMML) that is primarily based on clinical variables and examine additional impact from mutations and karyotype. 457 molecularly-annotated patients were considered. Multivariable analysis identified circulating Blasts ≥2% (1 point), Leukocytes ≥13 x 109/L (1 point), and severe (2 points) or moderate (1 point) Anemia as preferred risk variables in developing a clinical risk Stratification Tool for overall survival (OS), acronymized to "BLAST": low-risk (0 points; median 63 months); intermediate-risk (1 point; median 28 months; HR 2.2, 95% CI 1.6-3.0), and high-risk (2-4 points; median 13 months; 5.4, 4.1-7.3); the corresponding 3/5 year OS rates were 68%/53%, 43%/18%, and 12%/1%. BLAST model performance (AUC 0.77/0.85 at 3/5-years) was shown to be comparable to that of the molecular CMML-specific prognostic scoring system (CMML-mol; AUC 0.73/0.75) and the international prognostic scoring system-molecular (IPSS-M; AUC 0.73/0.74). Multivariable analysis of mutations and karyotype identified PHF6MUT and TET2MUT as being "favorable" and DNMT3AMUT, U2AF1MUT, BCORMUT, SETBP1MUT, ASXL1MUT, NRASMUT, PTPN11MUT, RUNX1MUT, TP53MUT, and adverse karyotype, "unfavorable". Molecular information was subsequently encoded in a combined clinical-molecular risk model (BLAST-mol; AUC 0.80/0.86 at 3/5-years) that included the aforementioned BLAST clinical risk variables and a 3-tiered molecular risk score. BLAST and BLAST-mol were subsequently validated by two separate external cohorts. Independent risk factors for blast transformation included DNMT3AMUT, ASXL1MUT, PHF6WT, leukocytes ≥13 x 109/L, and ≥2% circulating or ≥10% bone marrow blasts. The current study proposes an easy to implement, globally applicable, and molecularly adaptive risk model for CMML.