Hereditary hemochromatosis gene mutation in myelodysplastic syndrome

UVOD: Mijelodisplastični sindrom (MDS) je klonalna bolest hematopoetske matične stanice. Zbog potrebe za liječenjem transfuzijama krvi te intrinzičnih karakteristika patogeneze same bolesti, u sklopu MDS-a razvija se preopterećenje željezom i sekundarna hemokromatoza. Poznato je da točkaste mutacije HFE gena (C282Y i H63D) dovode do gomilanja željeza u organizmu i uzrok su hereditarne hemokromatoze (HH). Mutacije HFE gena moguće utječu i na tijek i prognozu MDS-a. ISPITANICI I METODE: Istraživanje je provedeno na 37 pacijenata dijagnosticiranih u KB Dubrava, Zagreb od 2008. godine nadalje. Pacijenti su genetski testirani na mutacije u HFE genu te su im analizirani parametri željeza i utjecaj mutacija na preživljenje i progresiju bolesti u leukemiju. REZULTATI: Dokazali smo da C282Y mutacija ima značajno nepovoljan učinak na preživljenje pacijenata s MDS-om, dok je učinak H63D mutacije na preživljenje granično nepovoljan. Dokazano je da H63D mutacija ima nepovoljan učinak u pogledu učestalosti progresije bolesti u akutnu mijelogenu leukemiju (AML). Nije dokazana statistički značajno učestalija mutiranost HFE gena u oboljelih od MDS-a u usporedbi sa zdravom hrvatskom populacijom. Analiza parametara metabolizma željeza pokazala je da pacijenti s H63D mutacijom imaju značajno niži TIBC, a podgrupa netransfudiranih s tom mutacijom značajno višu razinu feritina. Ostali parametri se nisu statistički značajno razlikovali između mutirane i nemutirane grupe pacijenata. RASPRAVA: U skladu s prijašnjim radovima, nismo dokazali povećanu učestalost HFE mutacija u oboljelih od MDS-a, ali smo također u skladu s već objavljenim rezultatima drugih autora dokazali da status mutiranosti HFE gena utječe na metabolizam željeza. Vjerojatno najvažniji rezultat ovog rada je nalaz nepovoljnog učinka HFE mutacija na ukupno preživljenje (OS, prema engl. overall survival) pacijenata što motivira pitanje treba li svakog oboljelog od MDS-a genetski testirati na HFE mutacije i je li racionalno u tih pacijenata ranije razmatrati terapiju kelatorima željeza. II ZAKLJUČAK: Broj mutiranih pojedinaca u grupi oboljelih od MDS-a viši je nego u grupi zdravih pojedinaca, no nismo uspjeli dokazati statistički značajnu razliku. HFE mutacije nepovoljno utječu na preživljenje pacijenata s MDS-om i progresiju bolesti u leukemiju. Također je primjećen utjecaj HFE mutacija na parametre željeza što vodi u opterećenje organizma željezom.INTRODUCTION: Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by abnormalities in hematopoietic stem cell. Many patients with MDS become transfusion therapy dependent and are prone to iron overload. The latter is caused by frequent transfusions and intrinsic characteristics of the disease. It is well known that HFE gene mutations (C282Y and H63D) lead to iron accumulation and cause hereditary hemochromatosis (HH). HFE gene mutations possibly affect disease course and prognosis of MDS. SUBJECTS AND METHODS: This research included 37 patients diagnosed with MDS in Clinical Hospital Dubrava, Zagreb, from 2008 to 2014. Patients were genetically tested for HFE gene mutations and effect of these mutations on iron metabolism parameters, overall survival (OS) and progression to leukemia were assesed. RESULTS: We have proved that C282Y mutation has significantly unfavourable effect on overall survival in patients with MDS. H63D mutation showes trend toward significance in OS when compared to wild type (wt) patients. We observed unfavourable effect of H63D mutation on MDS progression to leukemia frequency. HFE gene mutations incidence in healthy Croatian blood donors and in our patients does not differ significantly. Iron metabolism parameters analysis reveals that patients with H63D mutation have significantly lower TIBC levels and among them the transfusion naive patients have significantly higher ferritin levels. We did not observe statistically significant difference in other iron metabolism parameters. DISCUSSION: Our study found statistically insignificant difference in HFE mutations frequencies between healthy population and patients diagnosed with MDS. This observation is accordant with foreign authors' views and studies, as is our data that confirm evident effect of HFE mutations on iron metabolism. Probably the most notable finding of this study is the IV effect of HFE mutations on OS which is significantly worse in patients with mutated gene. These findings arouse dilemmas whether every MDS patient should be genetically tested for HFE mutations and whether earlier iron chelators therapy consideration in mutated patients is rational. CONCLUSION: A relative number of mutated individuals among MDS patients is higher than among healthy individuals but we were not able to prove statistically significant difference. HFE mutations have a poor effect on survival and progression to leukemia in MDS patients. Furthermore, HFE mutations' effect on iron parameters resulting in iron overload was noted

Hereditary hemochromatosis gene mutation in myelodysplastic syndrome

UVOD: Mijelodisplastični sindrom (MDS) je klonalna bolest hematopoetske matične stanice. Zbog potrebe za liječenjem transfuzijama krvi te intrinzičnih karakteristika patogeneze same bolesti, u sklopu MDS-a razvija se preopterećenje željezom i sekundarna hemokromatoza. Poznato je da točkaste mutacije HFE gena (C282Y i H63D) dovode do gomilanja željeza u organizmu i uzrok su hereditarne hemokromatoze (HH). Mutacije HFE gena moguće utječu i na tijek i prognozu MDS-a. ISPITANICI I METODE: Istraživanje je provedeno na 37 pacijenata dijagnosticiranih u KB Dubrava, Zagreb od 2008. godine nadalje. Pacijenti su genetski testirani na mutacije u HFE genu te su im analizirani parametri željeza i utjecaj mutacija na preživljenje i progresiju bolesti u leukemiju. REZULTATI: Dokazali smo da C282Y mutacija ima značajno nepovoljan učinak na preživljenje pacijenata s MDS-om, dok je učinak H63D mutacije na preživljenje granično nepovoljan. Dokazano je da H63D mutacija ima nepovoljan učinak u pogledu učestalosti progresije bolesti u akutnu mijelogenu leukemiju (AML). Nije dokazana statistički značajno učestalija mutiranost HFE gena u oboljelih od MDS-a u usporedbi sa zdravom hrvatskom populacijom. Analiza parametara metabolizma željeza pokazala je da pacijenti s H63D mutacijom imaju značajno niži TIBC, a podgrupa netransfudiranih s tom mutacijom značajno višu razinu feritina. Ostali parametri se nisu statistički značajno razlikovali između mutirane i nemutirane grupe pacijenata. RASPRAVA: U skladu s prijašnjim radovima, nismo dokazali povećanu učestalost HFE mutacija u oboljelih od MDS-a, ali smo također u skladu s već objavljenim rezultatima drugih autora dokazali da status mutiranosti HFE gena utječe na metabolizam željeza. Vjerojatno najvažniji rezultat ovog rada je nalaz nepovoljnog učinka HFE mutacija na ukupno preživljenje (OS, prema engl. overall survival) pacijenata što motivira pitanje treba li svakog oboljelog od MDS-a genetski testirati na HFE mutacije i je li racionalno u tih pacijenata ranije razmatrati terapiju kelatorima željeza. II ZAKLJUČAK: Broj mutiranih pojedinaca u grupi oboljelih od MDS-a viši je nego u grupi zdravih pojedinaca, no nismo uspjeli dokazati statistički značajnu razliku. HFE mutacije nepovoljno utječu na preživljenje pacijenata s MDS-om i progresiju bolesti u leukemiju. Također je primjećen utjecaj HFE mutacija na parametre željeza što vodi u opterećenje organizma željezom.INTRODUCTION: Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by abnormalities in hematopoietic stem cell. Many patients with MDS become transfusion therapy dependent and are prone to iron overload. The latter is caused by frequent transfusions and intrinsic characteristics of the disease. It is well known that HFE gene mutations (C282Y and H63D) lead to iron accumulation and cause hereditary hemochromatosis (HH). HFE gene mutations possibly affect disease course and prognosis of MDS. SUBJECTS AND METHODS: This research included 37 patients diagnosed with MDS in Clinical Hospital Dubrava, Zagreb, from 2008 to 2014. Patients were genetically tested for HFE gene mutations and effect of these mutations on iron metabolism parameters, overall survival (OS) and progression to leukemia were assesed. RESULTS: We have proved that C282Y mutation has significantly unfavourable effect on overall survival in patients with MDS. H63D mutation showes trend toward significance in OS when compared to wild type (wt) patients. We observed unfavourable effect of H63D mutation on MDS progression to leukemia frequency. HFE gene mutations incidence in healthy Croatian blood donors and in our patients does not differ significantly. Iron metabolism parameters analysis reveals that patients with H63D mutation have significantly lower TIBC levels and among them the transfusion naive patients have significantly higher ferritin levels. We did not observe statistically significant difference in other iron metabolism parameters. DISCUSSION: Our study found statistically insignificant difference in HFE mutations frequencies between healthy population and patients diagnosed with MDS. This observation is accordant with foreign authors' views and studies, as is our data that confirm evident effect of HFE mutations on iron metabolism. Probably the most notable finding of this study is the IV effect of HFE mutations on OS which is significantly worse in patients with mutated gene. These findings arouse dilemmas whether every MDS patient should be genetically tested for HFE mutations and whether earlier iron chelators therapy consideration in mutated patients is rational. CONCLUSION: A relative number of mutated individuals among MDS patients is higher than among healthy individuals but we were not able to prove statistically significant difference. HFE mutations have a poor effect on survival and progression to leukemia in MDS patients. Furthermore, HFE mutations' effect on iron parameters resulting in iron overload was noted

Hemochromatosis gene mutations may affect the survival of patients with myelodysplastic syndrome

OBJECTIVES: The recent availability of potent oral iron chelators is renewing an interest in the assessment of the possible impact of HFE genetics in MDS. ----- METHODS: Thirty six newly diagnosed patients with MDS were studied for parameters of iron metabolism in addition to C282Y and H63D mutations of the HFE gene. ----- RESULTS: Mutations were present in 11 out of 36 patients (31%), which were not different from our general population and were equally distributed among MDS subtypes. Mutated patients had higher ferritin levels (P = 0.039) and lower TIBC (P = 0.018). Ferritin was found to be higher for the untransfused mutated patients (P = 0.017), but not for transfusion-dependent patients in whom ferritin levels correlated significantly with the number of blood units received (P = 0.04). There was no difference in the number of blood units received between the mutated and wild type patients. A new observation made was that the mutated patients had a lower overall survival in addition to a poorer leukemia free survival (LFS) (P = 0.004 and P = 0.003, respectively). ----- DISCUSSION: The HFE gene mutations are not more frequent in MDS patients. Iron overload in mutated patients was higher but there was no correlation found using supportive therapy for anemia. The effect of mutations on survival could be mediated by changes in iron metabolism. ----- CONCLUSION: The HFE genotype may predict MDS prognosis and there is a need for further studies. It remains a challenging question if HFE mutated MDS patients should be considered for potent iron chelation therapy

The degree of anisocytosis predicts survival in patients with primary myelofibrosis

Introduction: Red cell distribution width (RDW) provides a quantitative measure of anisocytosis and it is associated with the presence of subclinical systemic inflammation and a poor outcome in a variety of diseases when elevated. Anisocytosis is a feature of primary myelofibrosis (PMF) but it’s prognostic role in PMF has not yet been evaluated. ----- Patients and methods: 33 newly-diagnosed patients with PMF were analyzed. Baseline RDW values were obtained in addition to CRP, LDH, complete blood count, iron metabolism parameters and JAK2 V617F mutational status. Patients were staged according to IPSS prognostic scoring system, liver and spleen size were assessed by palpation. ----- Results: Median RDW was 19.0% (15.2%-22.5%). RDW correlated significantly with hemoglobin level (p=0.005), CRP (p=0.031), spleen size (p=0.036) and IPSS score (p=0.003). Patients with more pronounced anisocytosis had an inferior overall survival (OS) – very-high RDW (≥19.0%) vs. high RDW (15.1%-18.9%) subgroup, HR 5.37, p=0.002. RDW remained significantly associated with OS (p=0.002) in a multivariate model including IPSS score, hemoglobin level and CRP. ----- Conclusion: A higher degree of anisocytosis is associated with more advanced disease features and a decreased overall survival. RDW encompasses standard prognostic score and may help in the rapid detection of patients with an unfavorable prognosis

Hereditary hemochromatosis gene mutation in myelodysplastic syndrome

UVOD: Mijelodisplastični sindrom (MDS) je klonalna bolest hematopoetske matične stanice. Zbog potrebe za liječenjem transfuzijama krvi te intrinzičnih karakteristika patogeneze same bolesti, u sklopu MDS-a razvija se preopterećenje željezom i sekundarna hemokromatoza. Poznato je da točkaste mutacije HFE gena (C282Y i H63D) dovode do gomilanja željeza u organizmu i uzrok su hereditarne hemokromatoze (HH). Mutacije HFE gena moguće utječu i na tijek i prognozu MDS-a. ISPITANICI I METODE: Istraživanje je provedeno na 37 pacijenata dijagnosticiranih u KB Dubrava, Zagreb od 2008. godine nadalje. Pacijenti su genetski testirani na mutacije u HFE genu te su im analizirani parametri željeza i utjecaj mutacija na preživljenje i progresiju bolesti u leukemiju. REZULTATI: Dokazali smo da C282Y mutacija ima značajno nepovoljan učinak na preživljenje pacijenata s MDS-om, dok je učinak H63D mutacije na preživljenje granično nepovoljan. Dokazano je da H63D mutacija ima nepovoljan učinak u pogledu učestalosti progresije bolesti u akutnu mijelogenu leukemiju (AML). Nije dokazana statistički značajno učestalija mutiranost HFE gena u oboljelih od MDS-a u usporedbi sa zdravom hrvatskom populacijom. Analiza parametara metabolizma željeza pokazala je da pacijenti s H63D mutacijom imaju značajno niži TIBC, a podgrupa netransfudiranih s tom mutacijom značajno višu razinu feritina. Ostali parametri se nisu statistički značajno razlikovali između mutirane i nemutirane grupe pacijenata. RASPRAVA: U skladu s prijašnjim radovima, nismo dokazali povećanu učestalost HFE mutacija u oboljelih od MDS-a, ali smo također u skladu s već objavljenim rezultatima drugih autora dokazali da status mutiranosti HFE gena utječe na metabolizam željeza. Vjerojatno najvažniji rezultat ovog rada je nalaz nepovoljnog učinka HFE mutacija na ukupno preživljenje (OS, prema engl. overall survival) pacijenata što motivira pitanje treba li svakog oboljelog od MDS-a genetski testirati na HFE mutacije i je li racionalno u tih pacijenata ranije razmatrati terapiju kelatorima željeza. II ZAKLJUČAK: Broj mutiranih pojedinaca u grupi oboljelih od MDS-a viši je nego u grupi zdravih pojedinaca, no nismo uspjeli dokazati statistički značajnu razliku. HFE mutacije nepovoljno utječu na preživljenje pacijenata s MDS-om i progresiju bolesti u leukemiju. Također je primjećen utjecaj HFE mutacija na parametre željeza što vodi u opterećenje organizma željezom.INTRODUCTION: Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder characterized by abnormalities in hematopoietic stem cell. Many patients with MDS become transfusion therapy dependent and are prone to iron overload. The latter is caused by frequent transfusions and intrinsic characteristics of the disease. It is well known that HFE gene mutations (C282Y and H63D) lead to iron accumulation and cause hereditary hemochromatosis (HH). HFE gene mutations possibly affect disease course and prognosis of MDS. SUBJECTS AND METHODS: This research included 37 patients diagnosed with MDS in Clinical Hospital Dubrava, Zagreb, from 2008 to 2014. Patients were genetically tested for HFE gene mutations and effect of these mutations on iron metabolism parameters, overall survival (OS) and progression to leukemia were assesed. RESULTS: We have proved that C282Y mutation has significantly unfavourable effect on overall survival in patients with MDS. H63D mutation showes trend toward significance in OS when compared to wild type (wt) patients. We observed unfavourable effect of H63D mutation on MDS progression to leukemia frequency. HFE gene mutations incidence in healthy Croatian blood donors and in our patients does not differ significantly. Iron metabolism parameters analysis reveals that patients with H63D mutation have significantly lower TIBC levels and among them the transfusion naive patients have significantly higher ferritin levels. We did not observe statistically significant difference in other iron metabolism parameters. DISCUSSION: Our study found statistically insignificant difference in HFE mutations frequencies between healthy population and patients diagnosed with MDS. This observation is accordant with foreign authors' views and studies, as is our data that confirm evident effect of HFE mutations on iron metabolism. Probably the most notable finding of this study is the IV effect of HFE mutations on OS which is significantly worse in patients with mutated gene. These findings arouse dilemmas whether every MDS patient should be genetically tested for HFE mutations and whether earlier iron chelators therapy consideration in mutated patients is rational. CONCLUSION: A relative number of mutated individuals among MDS patients is higher than among healthy individuals but we were not able to prove statistically significant difference. HFE mutations have a poor effect on survival and progression to leukemia in MDS patients. Furthermore, HFE mutations' effect on iron parameters resulting in iron overload was noted

CAR T Cell Therapy in Hematology: Navigating Toxicities and Deciphering Patient Experiences Through Patient-Reported Outcomes

This review examines the role of Patient-Reported Outcomes (PROs) in measuring toxicities of Chimeric Antigen Receptor T Cell Therapy (CAR T) for hematological malignancies. While highlighting the complex task of understanding the pathophysiology of CAR T’s unique adverse events (AEs), the discussion focuses on the need for precise characterization of the diverse symptomatology associated with individual CAR T syndromes and the importance of capturing patient experiences with these side effects using PRO instruments. This review underscores the continuous search for an ideal PRO tool that is effective in detecting both early changes and late toxicities; stressing the importance of monitoring PROs soon after therapy to gather data on acute toxicity, enabling timely interventions that could reduce symptom severity. The assessment of PROs at later stages is also highlighted as crucial for evaluating long-term quality of life (QoL), especially in terms of neurocognitive effects. The narrative review identifies a gap in current PRO tools not specifically tailored for CAR T therapy and calls for further research to develop a comprehensive set of symptoms for monitoring in various studies. Such efforts are vital for improving our understanding of therapy tolerability as well as for improving the treatment of these side effects. This would also enable the comparison of different CAR T products based on their response rates

Secondary polycythemia in acutely ill COVID-19 patients is associated with higher mortality but not markedly higher thrombotic risk

Secondary polycythemia is commonly observed among patients with chronic pulmonary diseases. However, its significance in the context of Coronavirus disease 2019 (COVID-19) is unknown. We retrospectively evaluated a total of 5872 hospitalized COVID-19 patients with mostly severe and critical symptoms, and without prior or subsequently diagnosed myeloproliferative neoplasm. Patients were stratified based on admission hemoglobin into four subgroups: anemia (hemoglobin 165 g/L for females and >185 g/L for males). Among 5872 patients, a total of 158 (2.7%) had mild and 25 (0.4%) severe polycythemia. Polycythemia was significantly associated with higher respiratory and functional impairment, reduced plasma volume, higher serum osmolarity and comorbidity burden specific to the degree of polycythemia. Patients presenting with mild (odds ratio (OR) = 1.63, p = .003) and severe polycythemia (OR = 4.98, p < .001) had increased risk of death in comparison to patients with normal hemoglobin, whereas no significant associations with venous thromboembolism, arterial thrombosis nor major bleeding were observed. Anemia was associated with higher risk of death (OR = 1.42, p < .001), venous thromboembolism (OR = 1.34, p < .006) and major bleeding (OR = 2.27, p < .001) in comparison to normal hemoglobin. Associations of polycythemia and anemia with mortality diminished, and anemia with venous thromboembolism and major bleeding persisted, after multivariate adjustments for age, sex, comorbidities, COVID-19 severity and functional status. Secondary polycythemia in hospitalized COVID-19 patients without prior of subsequently diagnosed myeloproliferative neoplasm is rare and is associated with high mortality, increasing with degree of polycythemia, but not markedly higher thrombotic ris

Hypoosmolar and hyperosmolar COVID-19 patients are predisposed to dismal clinical outcomes

We aimed to investigate the associations of hypo- and hyperosmolarity at hospital admission with clinical characteristics and outcomes in 5645 consecutive hospitalized COVID-19 patients treated at a tertiary-level institution. Serum osmolarity was calculated as 2x Na (mmol/L) + urea (mmol/L) + glucose (mmol/L), with normal range from 275 to 295 mOsm/L. Median serum osmolarity was 292.9 mOsm/L with 51.8% normoosmolar, 5.3% hypoosmolar and 42.9% hyperosmolar patients present at the time of hospital admission. Hypoosmolarity was driven by hyponatremia, and was associated with the presence of chronic liver disease, liver cirrhosis, active malignancy and epilepsy. Hyperosmolarity was driven by an increase in urea and glucose and was associated with the presence of chronic metabolic and cardiovascular comorbidities. Both hypo- and hyperosmolar patients presented with more severe COVID-19 symptoms, higher inflammatory status, and experienced higher mortality in comparison to normoosmolar patients. In multivariate analysis, hypoosmolarity (adjusted odds ratio (aOR)=1.39, p = 0.024) and hyperosmolarity (aOR = 1.9, p < 0.001) remained significantly associated with higher mortality independently of older age, male sex, higher Charlson Comorbidity Index and more severe COVID-19. Disruptions in serum osmolarity are frequent in COVID-19 patients, may be easy to detect and target therapeutically, and thus potentially moderate associateds poor prognosis