Paroxysmal nocturnal hemoglobinuria: Pandora’s box?

Introduction. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired non-malignant hematological disorder which affects the pluripotent hematopoietic stem cell. The cause of PNH development is the occurrence of somatic mutations in the phosphatidylinositol glycan-A gene which encodes a protein necessary for the biosynthesis of glycosylphosphatidylinositol anchors. The diagnosis of PNH requires the presence of signs of intravascular hemolysis, thrombosis, and (or) bone marrow failure. Case Report. We report the case of a 42-year-old female, diagnosed with PNH at the age of 27, whose evolution was initially characterized predominantly by hemolytic attacks and whose disease pattern evolved towards thromboembolic episodes with the advancement of age. Conclusions. Establishing the diagnosis of PNH is a difficult task and its management requires teamwork. During the evolution of the disease, a PNH patient can acquire supplementary risk factors for thrombosis, in addition to the pro-coagulant potential of the disease itself. We reported this case to remind physicians that establishing the diagnosis of PNH is troublesome, and thus it is questionable whether PNH is a rare disease or just underdiagnosed. In this context, in the clinical practice of hematologists and other physicians as well, PNH remains a veritable Pandora\u27s box

Determining diagnostic delays in Romanian multiple myeloma patients using the Aarhus statement

IntroductionMultiple Myeloma (MM) is classified as one of the most challenging cancers to diagnose, and the hematological malignancy is associated with prolonged diagnostic delays. Although major steps have been made in the improvement of MM patient diagnosis and care, Romanian patients still face long diagnostic delays. Thus far, there have been no studies evaluating the factors associated with diagnostic errors in Romanian MM patients.MethodsUsing the Aarhus statement, we prospectively determined the diagnostic intervals for 103 patients diagnosed with MM at Fundeni Clinical Institute, between January 2022 and March 2023.ResultsOur data revealed that the main diagnostic delays are experienced during the “patient interval.” Patients spend a median of 162 days from the first symptom onset until the first doctor appointment. Bone pain is the most frequently reported symptom by patients (78.64%), but it leads to a medical-seeking behavior in only half of the reporting patients and results in a median delay of 191 days. The changes in routine lab tests are considered most worrisome for patients, leading to a medical appointment after a median of only 25 days. The median primary care interval was 70 days, with patients having an average of 3.7 medical visits until MM suspicion was first raised. The secondary care interval did not contribute to the diagnostic delays.DiscussionOverall, the median diagnostic path for MM patients in Romania was more than 6 months, leading to a higher number of emergency presentations and myeloma-related end-organ damage

Patient Preferences for Multiple Myeloma Treatments : A Multinational Qualitative Study

Background: Investigational and marketed drugs for the treatment of multiple myeloma (MM) are associated with a range of characteristics and uncertainties regarding long term side-effects and efficacy. This raises questions about what matters most to patients living with this disease. This study aimed to understand which characteristics MM patients find most important, and hence should be included as attributes and levels in a subsequent quantitative preference survey among MM patients. Methods: This qualitative study involved: (i) a scoping literature review, (ii) discussions with MM patients (n = 24) in Belgium, Finland, Romania, and Spain using Nominal Group Technique, (iii) a qualitative thematic analysis including multi-stakeholder discussions. Results: MM patients voiced significant expectations and hopes that treatments would extend their lives and reduce their cancer signs and symptoms. Participants however raised concerns about life-threatening side-effects that could cause permanent organ damage. Bone fractures and debilitating neuropathic effects (such as chronic tingling sensations) were highlighted as major issues reducing patients' independence and mobility. Patients discussed the negative impact of the following symptoms and side-effects on their daily activities: thinking problems, increased susceptibility to infections, reduced energy, pain, emotional problems, and vision problems. MM patients were concerned with uncertainties regarding the durability of positive treatment outcomes, and the cause, severity, and duration of their symptoms and side-effects. Patients feared short-term positive treatment responses complicated by permanent, severe side-effects and symptoms. Conclusions: This study gained an in-depth understanding of the treatment and disease-related characteristics and types of attribute levels (severity, duration) that are most important to MM patients. Results from this study argue in favor of MM drug development and individual treatment decision-making that focuses not only on extending patients' lives but also on addressing those symptoms and side-effects that significantly impact MM patients' quality of life. This study underscores a need for transparent communication toward MM patients about MM treatment outcomes and uncertainties regarding their long-term efficacy and safety. Finally, this study may help drug developers and decision-makers understand which treatment outcomes and uncertainties are most important to MM patients and therefore should be incorporated in MM drug development, evaluation, and clinical practice.Peer reviewe

Impact of age on efficacy and toxicity of nilotinib in patients with chronic myeloid leukemia in chronic phase : ENEST1st subanalysis

Purpose Achievement of deep molecular response with a tyrosine kinase inhibitor in patients with chronic myeloid leukemia (CML) is required to attempt discontinuation of therapy in these patients. The current subanalysis from the Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study evaluated whether age has an impact on the achievement of deeper molecular responses or safety with frontline nilotinib in patients with CML. Methods ENEST1st is an open-label, multicenter, single-arm, prospective study of nilotinib 300 mg twice daily in patients with newly diagnosed CML in chronic phase. The patients were stratified into the following 4 groups based on age: young (18-39 years), middle age (40-59 years), elderly (60-74 years), and old (>= 75 years). The primary end point was the rate of molecular response 4 ([MR4] BCR-ABL1 Results Of the 1091 patients enrolled, 1089 were considered in the analysis, of whom, 23% (n = 243), 45% (n = 494), 27% (n = 300), and 5% (n = 52) were categorized as young, middle age, elderly, and old, respectively. At 18 months, the rates of MR4 were 33.9% (95% confidence interval [CI], 27.8-40.0%) in the young, 39.6% (95% CI, 35.3-44.0%) in the middle-aged, 40.5% (95% CI, 34.8-46.1%) in the elderly, and 35.4% (95% CI, 21.9-48.9%) in the old patients. Although the incidence of adverse events was slightly different, no new specific safety signals were observed across the 4 age groups. Conclusions This subanalysis of the ENEST1st study showed that age did not have a relevant impact on the deep molecular response rates associated with nilotinib therapy in newly diagnosed patients with CML and eventually on the eligibility of the patients to attempt treatment discontinuation.Peer reviewe

RNA sequencing suggests that non-coding RNAs play a role in the development of acquired haemophilia

Funding Information: Adrian Bogdan Tigu and Ionut Hotea contributed equally to the current manuscript and are both considered first author. The authors also gratefully acknowledge the support of Sergiu Pasca, M.D. – Johns Hopkins University School of Medicine, Baltimore, United States, for his contribution on the statistical analysis. Funding Information: IH is funded by an internal grant of the Iuliu Hatieganu University – School of Doctoral Studies. BT is supported by a national grant of the Romanian Academy of Scientists (Academia Oamenilor de Stiinta din Romania) 2023–2024. ABT, DG, JTB and VG are supported by an international collaborative grant of the European Economic Space between Romania and Iceland 2021–2023: ‘Cooperation strategy for knowledge transfer, internationalization and curricula innovation in the field of research education at the 3rd level of study –AURORA.’. The experiments were funded by an international grant awarded by the Novo Nordisk Haemophilia Foundation to the Romanian Haematology Society—Romania 4. CT is supported by a grant by grants awarded by the Romanian National Ministry of 350 Research, Innovation, and Digitalisation: Project PN‐III‐P4‐ID‐PCE‐2020‐1118. Publisher Copyright: © 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. © 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.Acquired haemophilia (AH) is a rare disorder characterized by bleeding in patients with no personal or family history of coagulation/clotting-related diseases. This disease occurs when the immune system, by mistake, generates autoantibodies that target FVIII, causing bleeding. Small RNAs from plasma collected from AH patients (n = 2), mild classical haemophilia (n = 3), severe classical haemophilia (n = 3) and healthy donors (n = 2), for sequencing by Illumina, NextSeq500. Based on bioinformatic analysis, AH patients were compared to all experimental groups and a significant number of altered transcripts were identified with one transcript being modified compared to all groups at fold change level. The Venn diagram shows that haemoglobin subunit alpha 1 was highlighted to be the common upregulated transcript in AH compared to classical haemophilia and healthy patients. Non-coding RNAs might play a role in AH pathogenesis; however, due to the rarity of HA, the current study needs to be translated on a larger number of AH samples and classical haemophilia samples to generate more solid data that can confirm our findings.Peer reviewe

SARS-CoV-2 infection in patients with multiple myeloma: survey in 23 centers across Europe and USA

Introduction: Despite several studies, the impact of coronavirus disease 2019 on patients with multiple myeloma remains uncertain. Material and methods: We performed a survey that covered the period of the first and second waves of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in 23 centers inseven countries. Out of 352 patients with myeloma and SARS-CoV-2, 23% died. Results/Conclusions: Logistic regression showed a lower risk of death among patients treated with proteasome inhibitor and a higher risk of death for those who had a severe or a very severe course of disease

Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study

Background Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. Methods In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0–2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Findings Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60–72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61–72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0–8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2–5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64–0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4–22·8) in the melflufen group and 16·3 months (10·1–23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1–25·6) at a median follow-up of 19·8 months (IQR 12·0–25·0) in the melflufen group and 25·0 months (95% CI 18·1–31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8–23·7; HR 1·10 [95% CI 0·85–1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). Interpretation Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma.Oncopeptides ABPeer reviewe

Comparison of two analytical methods (electrophoresis and HPLC) to detect thalassemias and hemoglobinopathies. Revista Română de Medicină de Laborator

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Case Series Using Salvage Haplo-Identical Stem Cells for Secondary Transplantation

In order to expand the donor pool and accessibility of the transplant procedure, it was necessary to introduce haplo-identical stem cell transplants in the Fundeni Clinical Institute from 2015. Even if the Romanian population is an ethnically compact white population, many of the patients referred for bone marrow transplant lack a suitable donor. Hematopoietic stem cell transplant from a haplo-identical donor is an alternative option for those patients without an HLA (Human Leucocyte Antigen)-matched donor (sibling or matched unrelated). This procedure was used also as a salvage option for those who experienced engraftment failure or the rejection of the first stem cell graft. In this case series, we present three such cases, with a haplo-transplant used as a salvage protocol (after an engraftment failure or rejection of the first transplanted cells). The patients we present were diagnosed with AML (acute myeloid leukemia) with MDS (myelodysplastic syndrome), MDS—RAEB 2 (myelodysplastic syndrome—refractory anemia with excess blasts 2), and SAA (severe aplastic anemia). In two of the three cases, the engraftment failure may have been due to the conditioning Fludarabine/Busulfan/Cyclophosphamide (Flu/Bu/CFA) used, combined with marrow grafts. In all three cases, the second transplant was of haplo-identical peripheral blood stem cells using Melphalan/Fludarabine (Mel/Flu) conditioning, the cells engrafted properly and the patients experienced complete chimerism, and two of them are alive with an excellent quality of life