Proof of concept of triple COMBI therapy to prohibit MPN progression to AML.

Patients with accelerated or blast phase myeloproliferative neoplasms have a dismal prognosis. The report by de Castro et al. provides important information on the rationale and prospect for a novel therapeutic approach combining interferon-alpha2 with 5-azacytidine and a JAK1-2 inhibitor (ruxolitinib) to be explored in well-designed clinical trials. Commentary on: Castro et al. Ratio of stemness to interferon signalling as a biomarker and therapeutic target of myeloproliferative neoplasm progression to acute myeloid leukaemia. Br J Haematol 2024;204:206-220.

JAK2V617F drives gut microbiota differences in patients with myeloproliferative neoplasms.

BACKGROUND: Essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (MF) are myeloproliferative neoplasms (MPN). Inflammation is involved in the initiation, progression, and symptomology of the diseases. The gut microbiota impacts the immune system, infection control, and steady-state hematopoiesis. METHODS: We analyzed the gut microbiota of 227 MPN patients and healthy controls (HCs) using next-generation sequencing. We expanded our previous results in PV and ET patients with additional PV, pre-MF, and MF patients which allowed us to compare MPN patients collectively, MPN sub-diagnoses, and MPN mutations (separately and combined) vs. HCs (N = 42) and compare within MPN sub-diagnoses and MPN mutation. RESULTS: MPN patients had a higher observed richness (median, 245 [range, 49-659]) compared with HCs (191.5 [range, 111-300; p = .003]) and a lower relative abundance of taxa within the Firmicutes phylum; for example, Faecalibacterium (6% vs. 14%, p < .001). The microbiota of CALR-positive patients (N = 30) resembled that of HCs more than that of patients with JAK2V617F (N = 177). In JAK2V617F-positive patients, only minor differences in the gut microbiota were observed between MPN sub-diagnoses, illustrating the importance of this mutation. CONCLUSION: The gut microbiota in MPN patients differs from HCs and is driven by JAK2V617F, whereas the gut microbiota in CALR patients resembles HCs more.

The pathobiology of thrombosis, microvascular disease, and hemorrhage in the myeloproliferative neoplasms.

Thrombotic, vascular, and bleeding complications are the most common causes of morbidity and mortality in the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). In these disorders, circulating red cells, leukocytes, and platelets, as well as some vascular endothelial cells, each have abnormalities that are cell-intrinsic to the MPN driver mutations they harbor (eg, JAK2 V617F). When these cells are activated in the MPNs, their interactions with each other create a highly proadhesive and prothrombotic milieu in the circulation that predisposes patients with MPN to venous, arterial, and microvascular thrombosis and occlusive disease. Bleeding problems in the MPNs are caused by the MPN blood cell-initiated development of acquired von Willebrand disease. The inflammatory state created by MPN stem cells in their microenvironment extends systemically to amplify the clinical thrombotic tendency and, at the same time, preferentially promote further MPN stem cell clonal expansion, thereby generating a vicious cycle that favors a prothrombotic state in these diseases.

Whole blood transcriptional profiling reveals highly deregulated atherosclerosis genes in Philadelphia-chromosome negative myeloproliferative neoplasms.

BACKGROUND: The Philadelphia-negative chronic myeloproliferative neoplasms (MPNs) are associated with a huge comorbidity burden, including an increased risk of cardiovascular diseases. Recently, chronic inflammation has been suggested to be the driving force for clonal evolution and disease progression in MPN but also potentially having an impact upon the development of accelerated (premature) atherosclerosis. OBJECTIVES: Since chronic inflammation, atherosclerosis, and atherothrombosis are prevalent in MPNs and we have previously shown oxidative stress genes to be markedly upregulated in MPNs, we hypothesized that genes linked to development of atherosclerosis might be highly deregulated as well. METHODS: Using whole blood gene expression profiling in patients with essential thrombocythemia (ET; n = 19), polycythemia vera (PV; n = 41), or primary myelofibrosis (PMF; n = 9), we herein for the first time report aberrant expression of several atherosclerosis genes. RESULTS: Of 84 atherosclerosis genes, 45, 56, and 46 genes were deregulated in patients with ET, PV, or PMF, respectively. Furthermore, BCL2L1, MMP1, PDGFA, PTGS1, and THBS4 were progressively significantly upregulated and BCL2 progressively significantly downregulated from ET over PV to PMF (all FDR <0.05). CONCLUSIONS: We have for the first time shown massive deregulation of atherosclerosis genes in MPNs, likely reflecting the inflammatory state in MPNs in association with in vivo activation of leukocytes, platelets, and endothelial cells being deeply involved in the atherosclerotic process.

Labor market affiliation of patients with myeloproliferative neoplasms: a population-based matched cohort study.

BACKGROUND: Patients with myeloproliferative neoplasms (MPNs) suffer from substantial symptoms and risk of debilitating complications, yet observational data on their labor market affiliation are scarce. MATERIAL AND METHODS: We conducted a descriptive cohort study using data from Danish nationwide registries, including patients diagnosed with MPN in 2010-2016. Each patient was matched with up to ten comparators without MPN on age, sex, level of education, and region of residence. We assessed pre- and post-diagnosis labor market affiliation, defined as working, unemployed, or receiving sickness benefit, disability pension, retirement pension, or other health-related benefits. Labor market affiliation was assessed weekly from two years pre-diagnosis until death, emigration, or 31 December 2018. For patients and comparators, we reported percentage point (pp) changes in labor market affiliation cross-sectionally from week -104 pre-diagnosis to week 104 post-diagnosis. RESULTS: The study included 3,342 patients with MPN and 32,737 comparators. From two years pre-diagnosis until two years post-diagnosis, a larger reduction in the proportion working was observed among patients than comparators (essential thrombocythemia: 10.2 [95% CI: 6.3-14.1] vs. 6.8 [95% CI: 5.5-8.0] pp; polycythemia vera: 9.6 [95% CI: 5.9-13.2] vs. 7.4 [95% CI: 6.2-8.7] pp; myelofibrosis: 8.1 [95% CI: 3.0-13.2] vs. 5.8 [95% CI: 4.2-7.5] pp; and unclassifiable MPN: 8.0 [95% CI: 3.0-13.0] vs. 7.4 [95% CI: 5.7-9.1] pp). Correspondingly, an increase in the proportion of patients receiving sickness benefits including other health-related benefits was evident around the time of diagnosis. CONCLUSION: Overall, we found that Danish patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN had slightly impaired labor market affiliation compared with a population of the same age and sex. From two years pre-diagnosis to two years post-diagnosis, we observed a larger reduction in the proportion of patients with MPN working and a greater proportion receiving sickness benefits compared with matched individuals.

Healthcare resource utilization in patients with myeloproliferative neoplasms: A Danish nationwide matched cohort study.

Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry-based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow-up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis.

Smoking impairs molecular response, and reduces overall survival in patients with chronic myeloproliferative neoplasms: A retrospective cohort study.

The effects of smoking on the molecular response (MR) and overall survival (OS) in patients with chronic myeloproliferative neoplasms (MPNs) have not been investigated before. We analysed a historical cohort of 498 consecutive patients diagnosed with MPNs. Moreover, we analysed a subgroup of 270 consecutive patients with MPNs with > 1 measurement of the JAK2V617F variant allele frequency. The data were analysed using Kaplan-Meier plots and Cox regression analysis, along with linear regression models. In all patients, the rate of MR was significantly higher in never-smokers compared with current smokers in the univariate model (HR, 1·9; 95% CI, 1·1-3·3; P = 0·033) and the multivariate model (HR, 1·9; 95% CI, 1·1-3·5; P = 0·029). Similar findings were observed with different cut-off values for a partial MR. A subgroup analysis including only interferon-α2-treated patients showed similar results. In multivariate analyses, the OS was significantly better for never-smokers (HR, 0·46; 95% CI, 0·29-0·75; P = 0·002) than current smokers. The differences were more pronounced in the pegylated interferon-α2-treated patients. However, no significant interaction of interferon-α2 treatment was observed. In conclusion, we found that tobacco smoking reduced the rate of MR and OS in patients with MPNs. Cessation of smoking should be encouraged.

Evidence of immune elimination, immuno-editing and immune escape in patients with hematological cancer.

There is mounting evidence that the immune system can spontaneously clear malignant lesions before they manifest as overt cancer, albeit this activity has been difficult to demonstrate in humans. The calreticulin (CALR) exon 9 mutations are driver mutations in patients with chronic myeloproliferative neoplasms (MPN), which are chronic blood cancers. The CALR mutations generate a neo-antigen that is recognized by patient T cells, and T cells isolated from a patient with a CALR-mutation can recognize and kill autologous CALR-mutant cells. Surprisingly, healthy individuals display frequent and strong T cell responses to the CALR neo-antigens too. Furthermore, healthy individuals display immune responses to all parts of the mutant CALR epitope, and the CALR neo-epitope specific responses are memory T cell responses. These data suggest that although healthy individuals might acquire a CALR mutation, the mutant cells can be eliminated by the immune system. Additionally, a small fraction of healthy individuals harbor a CALR exon 9 mutation. Four healthy individuals carrying CALR mutations underwent a full medical examination including a bone marrow biopsy after a median follow up of 6.2 years. None of these patients displayed any signs of CALR-mutant MPN. Additionally, all healthy individuals displayed strong CALR neo-epitope specific T cell responses suggesting that these healthy individuals retained their CALR-mutant cells in the editing stage for several years. Thus, we suggest that CALR-mutant MPN could be a disease model of cancer immuno-editing, as we have demonstrated that CALR-mutant MPN displays all three stages described in the theory of cancer immuno-editing.

Ruxolitinib and interferon-α2 combination therapy for patients with polycythemia vera or myelofibrosis: a phase II study.

We report the final 2-year end-of-study results from the first clinical trial investigating combination treatment with ruxolitinib and low-dose pegylated interferon-α2 (PEG-IFNα2). The study included 32 patients with polycythemia vera and 18 with primary or secondary myelofibrosis; 46 patients were previously intolerant of or refractory to PEGIFNα2. The primary outcome was efficacy, based on hematologic parameters, quality of life measurements, and JAK2 V617F allele burden. We used the 2013 European LeukemiaNet and International Working Group- Myeloproliferative Neoplasms Research and Treatment response criteria, including response in symptoms, splenomegaly, peripheral blood counts, and bone marrow. Of 32 patients with polycythemia vera, ten (31%) achieved a remission which was a complete remission in three (9%) cases. Of 18 patients with myelofibrosis, eight (44%) achieved a remission; five (28%) were complete remissions. The cumulative incidence of peripheral blood count remission was 0.85 and 0.75 for patients with polycythemia vera and myelofibrosis, respectively. The Myeloproliferative Neoplasm Symptom Assessment Form total symptom score decreased from 22 [95% confidence interval (95% CI):, 16-29] at baseline to 15 (95% CI: 10-22) after 2 years. The median JAK2 V617F allele burden decreased from 47% (95% CI: 33-61%) to 12% (95% CI: 6-22%), and 41% of patients achieved a molecular response. The drop-out rate was 6% among patients with polycythemia vera and 32% among those with myelofibrosis. Of 36 patients previously intolerant of PEG-IFNα2, 31 (86%) completed the study, and 24 (67%) of these received PEG-IFNα2 throughout the study. In conclusion, combination treatment improved cell counts, reduced bone marrow cellularity and fibrosis, decreased JAK2 V617F burden, and reduced symptom burden with acceptable toxicity in several patients with polycythemia vera or myelofibrosis. #EudraCT2013-003295-12.

Smoking and Increased White and Red Blood Cells.

Objective- Whether tobacco smoking causally affects white and red blood cells and thrombocyte counts is unknown. Using a Mendelian randomization approach, we tested the hypothesis that smoking causes increases in these blood cell indices. Approach and Results- We included 104 607 white Danes aged 20 to 100 years from the Copenhagen General Population Study with information on blood cell indices, smoking habits, and CHRNA3 (alpha 3 nicotinic cholinergic receptor) rs1051730 genotype, where the T allele causes higher tobacco consumption; 41 759 were former smokers and 17 852 current smokers. In multivariable adjusted observational analyses and compared with never smokers, white blood cells were associated with up to 19% increases, thrombocytes with up to 4.7% increases, and red blood cell indices with up to 2.3% increases in former and current smokers. All associations were dose dependent, with tobacco consumption but for white blood cells and thrombocytes also dependent on smoking cessation time in former smokers; highest increases were for <1-year smoking cessation and lowest increases for >10-year smoking cessation. In age- and sex-adjusted genetic analyses, percent differences per T allele increase in current smokers were 1.15% (95% CI, 0.61%-1.68%) for leukocytes, 1.07% (0.38%-1.76%) for neutrophils, 1.34% (0.66%-2.02%) for lymphocytes, 1.50% (0.83%-2.18%) for monocytes, -0.60% (-1.91% to 0.74%) for eosinophils, 0.17% (-0.94% to 1.29%) for basophils, 0.38% (-0.17% to 0.93%) for thrombocytes, 0.04% (-0.14% to 0.23%) for erythrocytes, 0.34% (0.17% to 0.50%) for hematocrit, 0.26% (0.09% to 0.43%) for hemoglobin, and 0.29% (0.18% to 0.41%) for mean corpuscular volume. Conclusions- Smoking causes increased blood leukocytes, neutrophils, lymphocytes, and monocytes, as well as increased hematocrit, hemoglobin, and mean corpuscular volume. The observational smoking relationships were long term for white blood cells and short term for red blood cell indices.

Cardiovascular disease in chronic myelomonocytic leukemia: do monocytosis and chronic inflammation predispose to accelerated atherosclerosis?

Patients with chronic myelomonocytic leukemia (CMML) have monocytosis and likely a state of chronic inflammation. Both have been associated with an increased risk of atherosclerosis. The aim of the study was to test the hypothesis that CMML patients are at increased risk of developing cardiovascular disease (CVD) due to persistent monocytosis and sustained chronic inflammation. In a retrospective cohort study, we assessed hazards for cardiovascular events after diagnosis in 112 CMML patients and 231 chronic lymphocytic leukemia (CLL) patients. Analyses were carried out on restricted cohorts (CMML = 84, CLL = 186), excluding patients with a prior history of CVD, as well as on unrestricted cohorts. In the restricted cohorts, a significant effect of cardiovascular event occurrence did not remain after adjustment (HR 2.49, 95% CI 0.94-6.60). In unrestricted cohorts, we found a more than twofold increased rate of cardiovascular events in CMML (HR 2.34, 95% CI 1.05-5.20). Our results indicate an increased risk of CVD after the diagnosis in CMML patients.

Myeloproliferative Neoplasms in Danish Twins.

OBJECTIVE: Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases characterized by clonal hyperproliferation of immature and mature cells of the myeloid lineage. Genetic differences have been proposed to play a role in the development of MPNs. Monozygotic twin pairs with MPNs have been reported in a few case reports, but the MPN concordance pattern in twins remains unknown. METHOD: All twin pairs born in the period 1900-2010 were identified in the nationwide Danish Twin Registry. Only pairs with both twins alive on January 1, 1977, and those born thereafter were included to allow identification in the Danish National Patient Registry. RESULTS: A total of 158 twin pairs were registered with an MPN diagnosis: 36 monozygotic, 104 dizygotic, and 18 pairs with unknown zygosity. MPNs were diagnosed in both twins in 4 pairs. The probandwise concordance rates for monozygotic twin pairs were higher than for dizygotic twin pairs (15 vs. 0%; p = 0.016). CONCLUSION: An estimated concordance rate of 15% (95% CI 0.059-0.31) is modest, but given the rarity of MPNs this finding is clinically relevant and provides further support for the role of genetic predisposition in the development of MPNs.

The effectiveness of exercise-based rehabilitation to patients with myeloproliferative neoplasms-An explorative study.

The aim of the study was to determine the impact of an interdisciplinary exercise-based rehabilitation intervention on fatigue and quality of life (QOL) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs). At the Danish Knowledge Centre for Rehabilitation and Palliative Care, a 5-day interdisciplinary exercise-based rehabilitation intervention was carried out on 48 patients with MPN. It was followed by 12 weeks of self-exercising prior to follow-up. Initially and at follow-up, participants filled out validated questionnaires; Brief Fatigue Inventory, Multidimensional Fatigue Inventory, European Organization for Research and Treatment of Cancer Quality-of-Life questionnaire, Myeloproliferative Neoplasm Symptom Assessment Form and Hospital Anxiety and Depression Scale. Maximal oxygen uptake and muscular strength were tested as well. Paired t test was used to compare scores between baseline and follow-up. In total, 45 participants (94%) completed the follow-up. No significant differences were observed on fatigue or QOL when comparing baseline and follow-up. Mean maximal oxygen uptake increased from 27.2 to 33.6 ml O2 · kg-1  ·min-1 (p < 0.001). Handgrip strength (p = 0.01) and the 30-s chair-stand test (p < 0.001) improved as well. No changes were found regarding levels of fatigue and QOL. However, we observed a significant increase in the physical capacity. Our observations call for further studies investigating the effects of non-pharmacological approaches in patients with MPN.

Second malignancies in hydroxyurea and interferon-treated Philadelphia-negative myeloproliferative neoplasms.

OBJECTIVE: In an era of controversy in regard to 'hydroxyurea-leukaemogenicity' and when interferon-alfa2 (IFN) is being revived in the treatment of Philadelphia-negative myeloproliferative neoplasms (MPNs), we aim in this single-centre observational study to describe the frequencies of second malignancies in a cohort of MPN patients treated with hydroxyurea (HU) or IFN monotherapy or the combination of these agents. PATIENTS AND METHODS: Records of a MPN cohort of 196 patients were reviewed, and a retrospective analysis was performed on 90 patients treated with HU, 38 patients treated with IFN and 68 patients treated with both IFN and HU. Logistic regression was used to compare frequencies in second malignancies. RESULTS: Patients treated with HU had a significantly higher risk of developing all second malignancies compared with patients treated with IFN [HU vs. IFN: OR of 4.01 (95%CI: 1.12-14.27, P-value: 0.023) and HU-IFN vs. IFN: OR 5.58 (95%CI: 1.55-20.15, P-value: 0.004)]. CONCLUSION: We have found an increased risk of second malignancies in MPN patients treated with HU compared with patients treated with IFN.

Increased iron stores prolong the QT interval - a general population study including 20 261 individuals and meta-analysis of thalassaemia major.

The prolongation of cardiac repolarization (QT interval) has been investigated in studies of patients with secondary iron overload. However, no previous population-based study examining the effect of increased iron stores on QT interval prolongation has previously been undertaken. We tested the hypothesis that increased iron stores and haemochromatosis genotype (genetically increased iron stores) are associated with prolongation of the QT interval. We included 20 261 individuals from the Danish General Suburban Population Study and examined differences in QT interval according to ferritin concentration, transferrin saturation, iron concentration, transferrin concentration and haemochromatosis genotype (C282Y/C282Y). Furthermore, we performed a meta-analysis of case-control studies on thalassaemia major patients and QT interval. Age- and C-reactive protein-adjusted mean corrected QT (QTc) intervals for ferritin concentration ≥99% vs. ≥25-<50% percentile were 418·9 ms vs. 412·7 ms in men (P < 0·001) and 422·4 ms vs. 419·1 ms in women (P = 0·78). Corresponding values for transferrin saturation were 417·6 ms vs. 412·6 ms in men (P = 0·02) and 421·5 ms vs. 419·4 ms in women (P = 0·86). The associations were not explained by inflammation and haemochromatosis genotype was not associated with QT interval length. In conclusion, increased iron stores, independent of haemochromatosis genotype and inflammation, are associated with prolongation of the QTc interval in men. This is a novel finding. In addition, the meta-analysis showed prolonged QT interval in thalassaemia major patients compared to healthy controls.

Smoking and philadelphia-negative chronic myeloproliferative neoplasms.

OBJECTIVE: A single-institution case-control study was conducted to test the hypothesis that a history of smoking was associated with a higher risk of developing MPNs compared to CLL. METHODS: Cases (n = 323) were all MPN patients diagnosed in a 10-year period, and controls (n = 333) were all patients with CLL diagnosed during that same period. Odds ratios and 95% confidence intervals were calculated and adjusted for gender and age by logistic regression. RESULTS: A significant association between a personal history of smoking and the risk of MPNs compared to CLL were observed for all MPNs (OR = 1.73, 95%CI 1.25-2.40) and for the WHO 2008 classified MPNs (OR = 1.64, 95%CI 1.16-2.30). CONCLUSIONS: No other larger case-control study has described a positive association between the risk of MPN and a history of smoking in the general MPN population. This association might be explained by the chronic inflammatory state and oxidative stress in response to smoking, eliciting genomic instability in the stem cell compartment and ultimately clonal evolution resulting in MPNs.

A new internet-based tool for reporting and analysing patient-reported outcomes and the feasibility of repeated data collection from patients with myeloproliferative neoplasms.

PURPOSE: An Internet-based tool for reporting and analysing patient-reported outcomes (PROs) has been developed. The tool enables merging PROs with blood test results and allows for computation of treatment responses. Data may be visualized by graphical analysis and may be exported for downstream statistical processing. The aim of this study was to investigate, whether patients with myeloproliferative neoplasms (MPNs) were willing and able to use the tool and fill out questionnaires regularly. METHODS: Participants were recruited from the outpatient clinic at the Department of Haematology, Roskilde University Hospital, Denmark. Validated questionnaires that were used were European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Myeloproliferative Neoplasm Symptom Assessment Form, Brief Fatigue Inventory and Short Form 36 Health Survey. Questionnaires were filled out ≥ 6 months online or on paper according to participant preference. Regularity of questionnaire submission was investigated, and participant acceptance was evaluated by focus-group interviews. RESULTS: Of 135 invited patients, 118 (87 %) accepted participation. One hundred and seven participants (91 %) preferred to use the Internet-based tool. Of the 118 enrolled participants, 104 (88 %) submitted PROs regularly ≥ 6 months. The focus-group interviews revealed that the Internet-based tool was well accepted. CONCLUSION: The Internet-based approach and regular collection of PROs are well accepted with a high participation rate, persistency and adherence in a population of MPN patients. The plasticity of the platform allows for adaptation to patients with other medical conditions.

Rituximab and dexamethasone vs dexamethasone monotherapy in newly diagnosed patients with primary immune thrombocytopenia.

In this study, we report the results from the largest cohort to date of newly diagnosed adult immune thrombocytopenia patients randomized to treatment with dexamethasone alone or in combination with rituximab. Eligible were patients with platelet counts ≤25×10(9)/L or ≤50×10(9)/L with bleeding symptoms. A total of 133 patients were randomly assigned to either dexamethasone 40 mg/day for 4 days (n = 71) or in combination with rituximab 375 mg/m(2) weekly for 4 weeks (n = 62). Patients were allowed supplemental dexamethasone every 1 to 4 weeks for up to 6 cycles. Our primary end point, sustained response (ie, platelets ≥50×10(9)/L) at 6 months follow-up, was reached in 58% of patients in the rituximab + dexamethasone group vs 37% in the dexamethasone group (P = .02). The median follow-up time was 922 days. We found longer time to relapse (P = .03) and longer time to rescue treatment (P = .007) in the rituximab + dexamethasone group. There was an increased incidence of grade 3 to 4 adverse events in the rituximab + dexamethasone group (P = .04). In conclusion, rituximab + dexamethasone induced higher response rates and longer time to relapse than dexamethasone alone. This study is registered at http://clinicaltrials.gov as NCT00909077.

MPNs as Inflammatory Diseases: The Evidence, Consequences, and Perspectives.

In recent years the evidence is increasing that chronic inflammation may be an important driving force for clonal evolution and disease progression in the Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Abnormal expression and activity of a number of proinflammatory cytokines are associated with MPNs, in particular MF, in which immune dysregulation is pronounced as evidenced by dysregulation of several immune and inflammation genes. In addition, chronic inflammation has been suggested to contribute to the development of premature atherosclerosis and may drive the development of other cancers in MPNs, both nonhematologic and hematologic. The MPN population has a substantial inflammation-mediated comorbidity burden. This review describes the evidence for considering the MPNs as inflammatory diseases, A Human Inflammation Model of Cancer Development, and the role of cytokines in disease initiation and progression. The consequences of this model are discussed, including the increased risk of second cancers and other inflammation-mediated diseases, emphasizing the urgent need for rethinking our therapeutic approach. Early intervention with interferon-alpha2, which as monotherapy has been shown to be able to induce minimal residual disease, in combination with potent anti-inflammatory agents such as JAK-inhibitors is foreseen as the most promising new treatment modality in the years to come.

The Role of Reactive Oxygen Species in Myelofibrosis and Related Neoplasms.

Reactive oxygen species (ROS) have been implicated in a wide variety of disorders ranging between traumatic, infectious, inflammatory, and malignant diseases. ROS are involved in inflammation-induced oxidative damage to cellular components including regulatory proteins and DNA. Furthermore, ROS have a major role in carcinogenesis and disease progression in the myeloproliferative neoplasms (MPNs), where the malignant clone itself produces excess of ROS thereby creating a vicious self-perpetuating circle in which ROS activate proinflammatory pathways (NF-κB) which in turn create more ROS. Targeting ROS may be a therapeutic option, which could possibly prevent genomic instability and ultimately myelofibrotic and leukemic transformation. In regard to the potent efficacy of the ROS-scavenger N-acetyl-cysteine (NAC) in decreasing ROS levels, it is intriguing to consider if NAC treatment might benefit patients with MPN. The encouraging results from studies in cystic fibrosis, systemic lupus erythematosus, and chronic obstructive pulmonary disease warrant such studies. In addition, the antioxidative potential of the widely used agents, interferon-alpha2, statins, and JAK inhibitors, should be investigated as well. A combinatorial approach using old agents with anticancer properties together with novel JAK1/2 inhibitors may open a new era for patients with MPNs, the outlook not only being "minimal residual disease" and potential cure but also a marked improvement in inflammation-mediated comorbidities.