Metformin use and risk of myeloproliferative neoplasms - a Danish population-based case-control study.

Previous studies have suggested that metformin has beneficial effects beyond its glucose-lowering properties, particularly in terms of its potential as an antineoplastic and cancer-preventive agent. In this study, we aimed to investigate the association between metformin use and the risk of myeloprolifera-tive neoplasms (MPN). We conducted a population-based case-control study utilizing Danish registers. Cases with MPN diagnosed between 2010-2018 were identified and metformin use prior to the MPN diagnosis was ascertained. We compared metformin use among cases with MPN and an age- and sex matched control group from the Danish general population to estimate age- and sex-adjusted odds ratios (ORs) and fully adjusted odds ratios (aORs) for the association between metformin use and risk of MPN. The study population included 3,816 cases and 19,080 controls. Overall, 7.0% of cases and 8.2% of controls were categorized as ever-users of metformin resulting in an OR for MPN of 0.84 (95% CI, 0.73-0.96) and an aOR of 0.70 (95% CI, 0.61-0.81). Long-term metformin use (≥5 years) was more infrequent and comprised 1.1% of cases and 2.0% of controls resulting in an OR of 0.57 (95% CI, 0.42-0.79) and an aOR of 0.45 (95% CI, 0.33-0.63). A dose-response relationship was observed when cumulative duration of treatment was analyzed, and this was consistent in stratified analyses of sex, age, and MPN subtypes. In conclusion, metformin use was associated with significantly lower odds of an MPN diagnosis, indi-cating its potential cancer-preventive effect. Due to the retrospective design, causality cannot be in-ferred.

Use of statins and risk of myeloproliferative neoplasms: a Danish nationwide case-control study.

Previous studies have indicated a possible cancer-protective effect of statins in solid cancers; however, this has never been investigated in myeloproliferative neoplasms (MPNs). We aimed to investigate the association between statin use and the risk of MPNs in a nested nationwide case-control study, using Danish national population registries. Information on statin use was obtained from the Danish National Prescription Registry, and patients diagnosed with MPNs between 2010 and 2018 were identified from the Danish National Chronic Myeloid Neoplasia Registry. The association between statin use and MPNs was estimated using age- and sex-adjusted odds ratios (ORs) and fully adjusted ORs (aORs), adjusting for prespecified confounders. The study population included 3816 cases with MPNs and 19 080 population controls (5:1) matched for age and sex using incidence density sampling. Overall, 34.9% of the cases and 33.5% of the controls ever used statins, resulting in an OR for MPN of 1.07 (95% confidence interval [CI], 0.99-1.16) and an aOR of 0.87 (95% CI, 0.80-0.96), respectively. 17.2% were categorized as long-term users (≥5 years) among the cases compared with 19.0% among controls, yielding an OR for MPN of 0.90 (95% CI, 0.81-1.00) and an aOR of 0.72 (95% CI, 0.64-0.81). Analysis of the effect of the cumulative duration of statin use revealed a dose-dependent response, and the association was consistent for sex, age, and MPN subgroups and across different statin types. Statin users were associated with significantly lower odds of being diagnosed with an MPN, indicating a possible cancer-preventive effect of statins. The retrospective of this study precludes causal inferences.

Genomic profiling of a randomized trial of interferon-α vs hydroxyurea in MPN reveals mutation-specific responses.

Although somatic mutations influence the pathogenesis, phenotype, and outcome of myeloproliferative neoplasms (MPNs), little is known about their impact on molecular response to cytoreductive treatment. We performed targeted next-generation sequencing (NGS) on 202 pretreatment samples obtained from patients with MPN enrolled in the DALIAH trial (A Study of Low Dose Interferon Alpha Versus Hydroxyurea in Treatment of Chronic Myeloid Neoplasms; #NCT01387763), a randomized controlled phase 3 clinical trial, and 135 samples obtained after 24 months of therapy with recombinant interferon-alpha (IFNα) or hydroxyurea. The primary aim was to evaluate the association between complete clinicohematologic response (CHR) at 24 months and molecular response through sequential assessment of 120 genes using NGS. Among JAK2-mutated patients treated with IFNα, those with CHR had a greater reduction in the JAK2 variant allele frequency (median, 0.29 to 0.07; P < .0001) compared with those not achieving CHR (median, 0.27 to 0.14; P < .0001). In contrast, the CALR variant allele frequency did not significantly decline in those achieving CHR or in those not achieving CHR. Treatment-emergent mutations in DNMT3A were observed more commonly in patients treated with IFNα compared with hydroxyurea (P = .04). Furthermore, treatment-emergent DNMT3A mutations were significantly enriched in IFNα-treated patients not attaining CHR (P = .02). A mutation in TET2, DNMT3A, or ASXL1 was significantly associated with prior stroke (age-adjusted odds ratio, 5.29; 95% confidence interval, 1.59-17.54; P = .007), as was a mutation in TET2 alone (age-adjusted odds ratio, 3.03; 95% confidence interval, 1.03-9.01; P = .044). At 24 months, we found mutation-specific response patterns to IFNα: (1) JAK2- and CALR-mutated MPN exhibited distinct molecular responses; and (2) DNMT3A-mutated clones/subclones emerged on treatment.

[Elevated blood cell counts and vascular disease with the myeloproliferative neoplasms as model diseases].

Recent studies have shown the Philadelphia-negative myeloproliferative neoplasms (MPN) to be massively underdiagnosed and often preceded by a long pre-diagnostic phase of several years, in which many patients suffer serious vascular events. In this review, we focus on the urgent need for earlier diagnosis and treatment of MPN. Such efforts are foreseen to decrease morbidity and mortality for the individual patients and potentially reduce costs for health and social care systems.

Introduction of a Comprehensive Diagnostic and Interdisciplinary Management Approach in Haematological Patients with Mucormycosis: A Pre and Post-Intervention Analysis.

Mucormycosis is a life threatening infection in patients with haematological disease. We introduced a Mucorales-PCR and an aggressive, multidisciplinary management approach for mucormycosis during 2016-2017 and evaluated patient outcomes in 13 patients diagnosed and treated in 2012-2019. Management principle: repeated surgical debridement until biopsies from the resection margins were clean as defined by negative Blankophor microscopy, Mucorales-PCR (both reported within 24 h), and cultures. Cultured isolates underwent EUCAST E.Def 9.3.1 susceptibility testing. Antifungal therapy (AFT) (mono/combination) combined with topical AFT (when possible) was given according to the minimal inhibitory concentration (MIC), severity of the infection, and for azoles, specifically, it was guided by therapeutic drug monitoring. The outcome was evaluated by case record review. All patients underwent surgery guided by diagnostic biopsies from tissue and resection margins (195 samples in total). Comparing 2012-2015 and 2016-2019, the median number of patients of surgical debridements was 3 and 2.5 and of diagnostic samples: microscopy/culture/PCR was 3/3/6 and 10.5/10/10.5, respectively. The sensitivity of microscopy (76%) and Mucorales-PCR (70%) were similar and microscopy was superior to that of culture (53%; p = 0.039). Initial systemic AFT was liposomal amphotericin B (n = 12) or posaconazole (n = 1) given as monotherapy (n = 4) or in combination with isavuconazole/posaconazole (n = 3/6) and terbinafine (n = 3). Nine patients received topical amphotericin B. All received isavuconazole or posaconazole consolidation therapy (n = 13). Mucormycosis related six month mortality was 3/5 in 2012-2015 and 0/7 patients in 2016-2019 (one patient was lost for follow-up). Implementation of combination therapy (systemic+topical AFT/combination systemic AFT) and aggressive surgical debridement guided by optimised diagnostic tests may improve the outcome of mucormycosis in haematologic patients.

Risks of Solid and Lymphoid Malignancies in Patients with Myeloproliferative Neoplasms: Clinical Implications.

In the past decade, several studies have reported that patients with chronic myeloproliferative neoplasms (MPNs) have an increased risk of second solid cancer or lymphoid hematological cancer. In this qualitative review study, we present results from studies that report on these cancer risks in comparison to cancer incidences in the general population or a control group. Our literature search identified 12 such studies published in the period 2009-2018 including analysis of more than 65,000 patients. The results showed that risk of solid cancer is 1.5- to 3.0-fold elevated and the risk of lymphoid hematological cancer is 2.5- to 3.5-fold elevated in patients with MPNs compared to the general population. These elevated risks apply to all MPN subtypes. For solid cancers, particularly risks of skin cancer, lung cancer, thyroid cancer, and kidney cancer are elevated. The largest difference in cancer risk between patients with MPN and the general population is seen in patients below 80 years. Cancer prognosis is negatively affected due to cardiovascular events, thrombosis, and infections by a concurrent MPN diagnosis mainly among patients with localized cancer. Our review emphasizes that clinicians caring for patients with MPNs should be aware of the very well-documented increased risk of second non-myeloid cancers.

Frequency and etiology of pulmonary hypertension in patients with myeloproliferative neoplasms.

OBJECTIVE: Pulmonary hypertension (PH) has been reported to be associated with myeloproliferative neoplasms (MPN), affecting 5%-48% of MPN patients. With the aims to describe the prevalence of PH in Ph-MPN patients and explore the cause in identified subjects, we performed a prospective cohort study of Ph-MPN patients. METHOD: Transthoracic echocardiography (TTE) was performed on all patients. When the TTE was abnormal, further investigations were performed according to current guidelines from the European Society of Cardiology. The primary endpoint was the frequency of PH. The secondary endpoint was causes of PH. RESULTS: We included 158 patients, median age was 65 years. Fifty percent had polycythemia vera, 34% essential thrombocytosis, and 11% primary myelofibrosis, 3% post-ET-myelofibrosis, and 2% post-PV-myelofibrosis. Only six patients (3.8%) were found to have a high probability of PH. They were all examined with right heart catheterization and all met the invasive criteria for PH. In all six patients other causes than MPN for PH were identified, although some contribution from the MPN could not be ruled out in three patients. CONCLUSION: In the largest study ever reported, we found a lower prevalence of PH (3.8%) than previously reported. Screening for PH in unselected MPN patients is not justified.