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Approximately 10% to 15% of patients with essential thrombocythemia (ET) lack the common driver mutations, so-called “triple-negative” (TN) disease. We undertook a systematic approach to investigate for somatic mutations and delineate gene expression signatures in 46 TN patients and compared the results to those with known driver mutations and healthy volunteers. Deep, error-corrected, next-generation sequencing of peripheral blood mononuclear cells using the HaloPlexHS platform and whole-exome sequencing was performed. Using this platform, 10 (22%) of 46 patients had detectable mutations (MPL, n = 6; JAK2V617F, n = 4) with 3 of 10 cases harboring germline MPL mutations. RNA-sequencing and DNA methylation analysis were also performed by using peripheral blood mononuclear cells. Pathway analysis comparing healthy volunteers and ET patients (regardless of mutational status) identified significant enrichment for genes in the tumor necrosis factor, NFκB, and MAPK pathways and upregulation of platelet proliferative drivers such as ITGA2B and ITGB3. Correlation with DNA methylation showed a consistent pattern of hypomethylation at upregulated gene promoters. Interrogation of these promoter regions highlighted enrichment of transcriptional regulators, which were significantly upregulated in patients with ET regardless of mutation status, including CEBPβ and NFκB. For “true” TN ET, patterns of gene expression and DNA methylation were similar to those in ET patients with known driver mutations. These observations suggest that the resultant ET phenotype may, at least in part and regardless of mutation type, be driven by transcriptional misregulation and may propagate downstream via the MAPK, tumor necrosis factor, and NFκB pathways with resultant JAK-STAT activation. These findings identify potential novel mechanisms of disease initiation that require further evaluation.

Approximately 10% to 15% of patients with essential thrombocythemia (ET) lack the common driver mutations, so-called “triple-negative” (TN) disease. We undertook a systematic approach to investigate for somatic mutations and delineate gene expression signatures in 46 TN patients and compared the results to those with known driver mutations and healthy volunteers. Deep, error-corrected, next-generation sequencing of peripheral blood mononuclear cells using the HaloPlexHSplatform and whole-exome sequencing was performed. Using this platform, 10 (22%) of 46 patients had detectable mutations (MPL,n = 6; JAK2V617F, n = 4) with 3 of 10 cases harboring germline MPLmutations. RNA-sequencing and DNA methylation analysis were also performed by using peripheral blood mononuclear cells. Pathway analysis comparing healthy volunteers and ET patients (regardless of mutational status) identified significant enrichment for genes in the tumor necrosis factor, NFκB, and MAPK pathways and upregulation of platelet proliferative drivers such as ITGA2Band ITGB3. Correlation with DNA methylation showed a consistent pattern of hypomethylation at upregulated gene promoters. Interrogation of these promoter regions highlighted enrichment of transcriptional regulators, which were significantly upregulated in patients with ET regardless of mutation status, including CEBPβ and NFκB. For “true” TN ET, patterns of gene expression and DNA methylation were similar to those in ET patients with known driver mutations. These observations suggest that the resultant ET phenotype may, at least in part and regardless of mutation type, be driven by transcriptional misregulation and may propagate downstream via the MAPK, tumor necrosis factor, and NFκB pathways with resultant JAK-STAT activation. These findings identify potential novel mechanisms of disease initiation that require further evaluation.

Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABLin the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P< .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P= .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P< .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P= .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P= .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).

Relapse remains the most common cause of treatment failure for patients with acute myeloid leukemia (AML) who undergo allogeneic stem cell transplantation (alloSCT), and carries a grave prognosis. Multiple studies have identified the presence of measurable residual disease (MRD) assessed by flow cytometry before alloSCT as a strong predictor of relapse, but it is not clear how these findings apply to patients who test positive in molecular MRD assays, which have far greater sensitivity. We analyzed pretransplant blood and bone marrow samples by reverse-transcription polymerase chain reaction in 107 patients with NPM1-mutant AML enrolled in the UK National Cancer Research Institute AML17 study. After a median follow-up of 4.9 years, patients with negative, low (<200 copies per 105ABL in the peripheral blood and <1000 copies in the bone marrow aspirate), and high levels of MRD had an estimated 2-year overall survival (2y-OS) of 83%, 63%, and 13%, respectively (P < .0001). Focusing on patients with low-level MRD before alloSCT, those with FLT3 internal tandem duplications(ITDs) had significantly poorer outcome (hazard ratio [HR], 6.14; P = .01). Combining these variables was highly prognostic, dividing patients into 2 groups with 2y-OS of 17% and 82% (HR, 13.2; P < .0001). T-depletion was associated with significantly reduced survival both in the entire cohort (2y-OS, 56% vs 96%; HR, 3.24; P = .0005) and in MRD-positive patients (2y-OS, 34% vs 100%; HR, 3.78; P = .003), but there was no significant effect of either conditioning regimen or donor source on outcome. Registered at ISRCTN (http://www.isrctn.com/ISRCTN55675535).

Pregnancy in myeloproliferative neoplasms (MPN) is commonly associated with maternal and foetal complications due to increased risks of thromboembolic and haemorrhagic events and placental dysfunction. The incidence of UK pregnancies in MPN is estimated as 3·2/100 000 maternities per year (Alimam, S., et al2016, Br J Haematol 2016; 175:31-36; Robinson et al, Br J Haematol 2020;189:625-34). Here we present pregnancy outcomes of MPN patients attending University College London Hospital (UCLH), a large UK tertiary referral centre, between 2015 and 2023.

Classical ‘Philadelphia negative’ myeloproliferative neoplasms (MPNs) are clonal haematopoietic disorders and include essential thrombocythaemia (ET), polycythaemia vera (PV) and myelofibrosis (MF). MPNs have a heterogenous phenotype with an inherent risk of thromboembolic and haemorrhagic complications, and risk of blastic transformation. MPNs are commonly diagnosed in the 6 thdecade or later, although up to 20% of patients are diagnosed < 40 years. Current risk stratification and treatment guidance, however, is frequently extrapolated from older cohorts.

Introduction

Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis, and leukemia. Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET and polycythemia vera patients resistant or intolerant to HC. Here, findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively. There was no evidence of improvement in complete response within 1 year reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT (P= .40). At 2 years, rates of thrombosis, hemorrhage, and transformation were not significantly different; however, some disease-related symptoms improved in patients receiving ruxolitinib relative to BAT. Molecular responses were uncommon; there were 2 complete molecular responses (CMR) and 1 partial molecular response in CALR-positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in 1 CMR patient, presumably because of the emergence of a different clone, raising questions about the relevance of CMR in ET patients. Grade 3 and 4 anemia occurred in 19% and 0% of ruxolitinib vs 0% (both grades) in the BAT arm, and grade 3 and 4 thrombocytopenia in 5.2% and 1.7% of ruxolitinib vs 0% (both grades) of BAT-treated patients. Rates of discontinuation or treatment switching did not differ between the 2 trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET. This trial was registered at www.isrctn.comas #ISRCTN61925716.

Treatments for high-risk essential thrombocythemia (ET) address thrombocytosis, disease-related symptoms, as well as risks of thrombosis, hemorrhage, transformation to myelofibrosis, and leukemia. Patients resistant/intolerant to hydroxycarbamide (HC) have a poor outlook. MAJIC (ISRCTN61925716) is a randomized phase 2 trial of ruxolitinib (JAK1/2 inhibitor) vs best available therapy (BAT) in ET and polycythemia vera patients resistant or intolerant to HC. Here, findings of MAJIC-ET are reported, where the modified intention-to-treat population included 58 and 52 patients randomized to receive ruxolitinib or BAT, respectively. There was no evidence of improvement in complete response within 1 year reported in 27 (46.6%) patients treated with ruxolitinib vs 23 (44.2%) with BAT (P = .40). At 2 years, rates of thrombosis, hemorrhage, and transformation were not significantly different; however, some disease-related symptoms improved in patients receiving ruxolitinib relative to BAT. Molecular responses were uncommon; there were 2 complete molecular responses (CMR) and 1 partial molecular response in CALR-positive ruxolitinib-treated patients. Transformation to myelofibrosis occurred in 1 CMR patient, presumably because of the emergence of a different clone, raising questions about the relevance of CMR in ET patients. Grade 3 and 4 anemia occurred in 19% and 0% of ruxolitinib vs 0% (both grades) in the BAT arm, and grade 3 and 4 thrombocytopenia in 5.2% and 1.7% of ruxolitinib vs 0% (both grades) of BAT-treated patients. Rates of discontinuation or treatment switching did not differ between the 2 trial arms. The MAJIC-ET trial suggests that ruxolitinib is not superior to current second-line treatments for ET. This trial was registered at www.isrctn.com as #ISRCTN61925716.

Polycythaemia vera (PV) is a myeloproliferative neoplasm classically characterized by an erythrocytosis and is associated with a high risk of thromboembolic events, constitutional symptoms burden and risk of transformation to myelofibrosis and acute myeloid leukaemia. Therapy is directed at the haematocrit (HCT) to reduce the risk of thrombotic events and usually comprises low-dose aspirin and phlebotomy to maintain HCT at >45%. Frequently in addition, cytoreductive therapy is indicated in high-risk patients for normalizing haematological parameters to mitigate the occurrence of thromboembolic events. Unfortunately, there is no clear evidence that current therapies reduce the risk of transformation to myelofibrosis and for some a risk of a therapy related complication is unknown for example leukaemia due to hydroxycarbamide (HC). First-line therapy for treating PV remains HC or interferon, the latter most often in younger patients, especially those of childbearing age. However, therapy related intolerance or resistance is a common feature and results in limited treatment options for such patients. The discovery of the JAK2 V617F mutation and consequently targeted therapy with Janus kinase inhibitors, in particular ruxolitinib, has extended the spectrum of agents that can be used as second or third line in PV. The findings of the phase II trial RESPONSE and the preliminary data from RESPONSE 2 trial have identified a role for ruxolitinib in PV patients who are resistant or intolerant to HC. In this article, using clinical cases we demonstrate our experience with ruxolitinib highlighting the clinical benefits and limitations we encountered in clinical practice.

We performed a meta-analysis to evaluate the risk of venous thromboembolism (VTE) in pregnant women with essential thrombocythemia. Twenty-one trials and 756 pregnancies met inclusion criteria. The absolute VTE risk in the antepartum period is not above a threshold where low-molecular-weight heparin (LMWH) prophylaxis is clearly indicated or below a threshold where LMWH should be withheld (2.5%; 95% CI, 1.3-4.3). Postpartum, the absolute VTE risk is above a threshold where postpartum LMWH prophylaxis should be considered (4.4%; 95% CI, 1.2-9.5).

We performed a meta-analysis to evaluate the risk of venous thromboembolism (VTE) in pregnant women with essential thrombocythemia. Twenty-one trials and 756 pregnancies met inclusion criteria. The absolute VTE risk in the antepartum period is not above a threshold where low-molecular-weight heparin (LMWH) prophylaxis is clearly indicated or below a threshold where LMWH should be withheld (2.5%; 95% CI, 1.3-4.3). Postpartum, the absolute VTE risk is above a threshold where postpartum LMWH prophylaxis should be considered (4.4%; 95% CI, 1.2-9.5).

Sekhar: Novartis: Consultancy, Research Funding.

Dillon: Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; TEVA: Consultancy, Honoraria. Radia:Blueprint Medicines: Consultancy; Novartis: Consultancy, Speakers Bureau. De Lavallade:BMS: Honoraria, Research Funding, Speakers Bureau; Incyte biosciences: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Harrison:Incyte: Speakers Bureau; AOP: Honoraria; Gilead: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Sierra Oncology: Honoraria; Promedior: Honoraria; Roche: Honoraria; Janssen: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; CTI: Speakers Bureau; Shire: Speakers Bureau. Kordasti:Celgene: Research Funding; Novartis: Research Funding; Boston Biomed: Consultancy; API: Consultancy. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria.

Background

Harrison: Gilead: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau. Mead:ARIAD: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy; Cell Therapeutics: Consultancy; Celgene: Research Funding; Elstar: Research Funding; Evotek: Research Funding.

Carrier: BMS: Research Funding; Leo Pharma: Research Funding. Robinson:Novartis: Honoraria; Pharmacosmos: Honoraria; Amgen: Honoraria. Rodger:Boehringer Ingelheim: Research Funding; Canadian Agency for Drugs and Technologies in Health: Consultancy.

Introduction:There is an increased risk of venous thromboembolism (VTE) in patients with essential thrombocythemia (ET), however, what the absolute VTE risk is during pregnancy is largely unknown and is based on small cohort or registry studies. Recommendation for the use of low-molecular-weight heparin (LMWH) prophylaxis in the antepartum and/or postpartum setting is based on the absolute VTE and bleeding risk in other patient populations, for example, in women with inherited thrombophilia. A better estimate of absolute VTE risk will provide guidance for the use of LMWH in pregnant women with ET, as well as other treatments such as interferon.

Harrison: Shire: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau.

Introduction