94 results on '"Kulasekararaj, A."'
Search Results
2. Comparative clinical efficacy and safety of biosimilar ABP 959 and eculizumab reference product in patients with paroxysmal nocturnal hemoglobinuria.
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Kulasekararaj A, Lanza F, Arvanitakis A, Langemeijer S, Chonat S, Tombak A, Hanes V, Cao J, Miller MJ, Colbert A, Shander B, Mytych DT, Chow V, and Henary H
- Abstract
ABP 959 is a biosimilar to the eculizumab reference product (RP), which is approved for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH). This multicenter, randomized, double-blind, active-controlled, two-period crossover study randomized eculizumab RP-treated patients with PNH to one of two treatment sequences (ABP 959/eculizumab RP or eculizumab RP/ABP 959) to evaluate the clinical similarity of ABP 959 when compared with eculizumab RP. This study evaluated the efficacy of ABP 959 when compared with eculizumab RP based on control of intravascular hemolysis as measured by lactate dehydrogenase (LDH) and by the time-adjusted area under the effect curve of LDH. Secondary outcomes included safety, pharmacokinetics, and immunogenicity. Forty-two patients were randomized (20 in the ABP 959/eculizumab RP group and 22 in the eculizumab RP/ABP 959 group) across 25 centers. Similarity of efficacy was established by a ratio of geometric least squares means of LDH (ABP 959/eculizumab RP) of 1.0628, with a one-sided 97.5% upper CI of 1.1576 at week 27, and a geometric means ratio of time-adjusted area under the effect curve (ABP 959 vs. eculizumab RP) of LDH of 0.981, with a 90% CI of 0.9403-1.0239 from week 13 to 27, week 39 to 53, and week 65 to 79. All secondary efficacy endpoints were comparable between treatment groups. No new safety concerns were identified. The results of this study in patients with PNH, along with previously demonstrated similarity of analytical, nonclinical, and clinical pharmacokinetics and pharmacodynamics in healthy volunteers support a demonstration of no clinically meaningful differences between ABP 959 and eculizumab RP. Clinical Trial Registration: NCT03818607., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)
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- 2024
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3. Moving toward Individual Treatment Goals with Pegcetacoplan in Patients with PNH and Impaired Bone Marrow Function.
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Szer J, Panse J, Kulasekararaj A, Oliver M, Fattizzo B, Nishimura JI, Horneff R, Szamosi J, and Peffault de Latour R
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- Humans, Male, Female, Middle Aged, Adult, Hemoglobins metabolism, Aged, Complement C3 metabolism, Treatment Outcome, Quality of Life, L-Lactate Dehydrogenase blood, L-Lactate Dehydrogenase metabolism, Hemoglobinuria, Paroxysmal, Bone Marrow metabolism
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Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, potentially life-threatening haematological disease characterised by chronic complement-mediated haemolysis with multiple clinical consequences that impair quality of life. This post hoc analysis assessed haematological and clinical responses to the first targeted complement C3 inhibitor pegcetacoplan in patients with PNH and impaired bone marrow function in the PEGASUS (NCT03500549) and PRINCE (NCT04085601) studies. For patients with impaired bone marrow function, defined herein as haemoglobin <10 g/dL and absolute neutrophil count <1.5 × 10
9 cells/L, normalisation of the parameters may be difficult. Indeed, 20% and 43% had normalised haemoglobin in PEGASUS and PRINCE, respectively; 60% and 57% had normalised LDH, and 40% and 29% had normalised fatigue scores. A new set of parameters was applied using changes associated with clinically meaningful improvements, namely an increase in haemoglobin to ≥2 g/dL above baseline, decrease in LDH to ≤1.5× the upper limit of normal, and an increase in fatigue scores to ≥5 points above baseline. With these new parameters, 40% and 71% of PEGASUS and PRINCE patients had improved haemoglobin; 60% and 71% had an improvement in LDH, and 60% and 43% had an improvement in fatigue scores. Thus, even patients with impaired bone marrow function may achieve clinically meaningful improvements with pegcetacoplan.- Published
- 2024
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4. Pregnancy in acquired bone marrow failure syndromes: Antenatal management and maternal and fetal outcomes.
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Bortolotti M, Trikha R, Salter S, Large J, Vlachodimitropoulou E, Gandhi S, Barcellini W, Johns J, Fattizzo B, and Kulasekararaj A
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- Humans, Pregnancy, Female, Adult, Pregnancy Outcome, Pregnancy Complications, Hematologic therapy, Bone Marrow Diseases, Anemia, Aplastic therapy, Infant, Newborn, Hemoglobinuria, Paroxysmal therapy, Hemoglobinuria, Paroxysmal diagnosis, Bone Marrow Failure Disorders
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- 2024
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5. Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT.
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Montoro J, Eikema DJ, Tuffnell J, Potter V, Kalwak K, Halkes CJM, Kulagin A, Collin M, Wynn RF, Robinson S, Nicholson E, Sengeloev H, Clay J, Halahleh K, Skorobogatova E, Sanz J, Passweg J, Mielke S, Ryhänen S, Carpenter B, Gedde-Dahl T, Tholouli E, Fanin R, Lewalle P, Kulasekararaj A, Risitano A, and Peffault de Latour R
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- Humans, Female, Male, Adult, Adolescent, Middle Aged, Young Adult, Child, Child, Preschool, Transplantation, Haploidentical methods, Tissue Donors, Anemia, Aplastic therapy, Anemia, Aplastic mortality, Unrelated Donors, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation methods
- Abstract
Abstract: Selecting the most suitable alternative donor becomes challenging in severe aplastic anemia (SAA) when a matched sibling donor (MSD) is unavailable. We compared outcomes in patients with SAA undergoing stem cell transplantation (SCT) from matched unrelated donors (MUD) (n = 1106), mismatched unrelated donors (MMUD) (n = 340), and haploidentical donors (Haplo) (n = 206) registered in the European Society for Blood and Marrow Transplantation database (2012-2021). For Haplo SCT, only those receiving posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis were included. Median age was 20 years, and the median time from diagnosis to transplantation 8.7 months. Compared with MUD, MMUD (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.52-5.6) and Haplo (HR, 5.15; 95% CI, 2.5-10.58) showed significantly higher risks of primary graft failure. MUD had lower rates of acute GVHD compared with MMUD and Haplo (grade 2-4: 13%, 22%, and 19%, respectively; P < .001; grade 3-4: 5%, 9%, and 7%, respectively; P = .028). The 3-year nonrelapse mortality rate was 14% for MUD, 19% for MMUD, and 27% for Haplo (P < .001), whereas overall survival and GVHD and relapse-free survival (GRFS) rates were 81% and 73% for MUD, 74% and 65% for MMUD, and 63% and 54% for Haplo, respectively (P < .001). In addition to donor type, multivariable analysis identified other factors associated with GRFS such as patient age, performance status, and interval between diagnosis and transplantation. For patients with SAA lacking an MSD, our findings support MUDs as the preferable alternative donor option. However, selecting between an MMUD and Haplo donor remains uncertain and requires further exploration., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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6. Correction: Need for ICU and outcome of critically ill patients with COVID-19 and haematological malignancies: results from the EPICOVIDEHA survey.
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Lahmer T, Salmanton-García J, Marchesi F, El-Ashwah S, Nucci M, Besson C, Itri F, Jaksic O, Čolović N, Weinbergerová B, Seval GC, Adžić-Vukičević T, Szotkowski T, Sili U, Dargenio M, van Praet J, van Doesum J, Schönlein M, Ráčil Z, Žák P, Poulsen CB, Magliano G, Jiménez M, Bonuomo V, Piukovics K, Dragonetti G, Demirkan F, Blennow O, Valković T, Gomes Da Silva M, Maertens J, Glenthøj A, Fernández N, Bergantim R, Verga L, Petzer V, Omrani AS, Méndez GA, Machado M, Ledoux MP, Bailén R, Duarte RF, Del Principe MI, Farina F, Martín-Pérez S, Dávila-Valls J, Marchetti M, Bilgin YM, Fracchiolla NS, Cattaneo C, Espigado I, Cordoba R, Collins GP, Labrador J, Falces-Romero I, Prezioso L, Meers S, Passamonti F, Buquicchio C, López-García A, Kulasekararaj A, Ormazabal-Vélez I, Cuccaro A, Garcia-Vidal C, Busca A, Navrátil M, de Jonge N, Biernat MM, Guidetti A, Abu-Zeinah G, Samarkos M, Anastasopoulou A, de Ramón C, González-López TJ, Hoenigl M, Finizio O, Pinczés LI, Ali N, Vena A, Tascini C, Stojanoski Z, Merelli M, Emarah Z, Kohn M, Barać A, Mladenović M, Mišković B, Ilhan O, Çolak GM, Čerňan M, Gräfe SK, Ammatuna E, Hanakova M, Víšek B, Cabirta A, Nordlander A, Nunes Rodrigues R, Hersby DS, Zambrotta GPM, Wolf D, Núñez-Martín-Buitrago L, Arellano E, Aiello TF, García-Sanz R, Prattes J, Egger M, Limongelli A, Bavastro M, Cvetanoski M, Dibos M, Rasch S, Rahimli L, Cornely OA, and Pagano L
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- 2024
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7. Need for ICU and outcome of critically ill patients with COVID-19 and haematological malignancies: results from the EPICOVIDEHA survey.
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Lahmer T, Salmanton-García J, Marchesi F, El-Ashwah S, Nucci M, Besson C, Itri F, Jaksic O, Čolović N, Weinbergerová B, Seval GC, Adžić-Vukičević T, Szotkowski T, Sili U, Dargenio M, van Praet J, van Doesum J, Schönlein M, Ráčil Z, Žák P, Poulsen CB, Magliano G, Jiménez M, Bonuomo V, Piukovics K, Dragonetti G, Demirkan F, Blennow O, Valković T, Gomes Da Silva M, Maertens J, Glenthøj A, Fernández N, Bergantim R, Verga L, Petzer V, Omrani AS, Méndez GA, Machado M, Ledoux MP, Bailén R, Duarte RF, Del Principe MI, Farina F, Martín-Pérez S, Dávila-Valls J, Marchetti M, Bilgin YM, Fracchiolla NS, Cattaneo C, Espigado I, Cordoba R, Collins GP, Labrador J, Falces-Romero I, Prezioso L, Meers S, Passamonti F, Buquicchio C, López-García A, Kulasekararaj A, Ormazabal-Vélez I, Cuccaro A, Garcia-Vidal C, Busca A, Navrátil M, de Jonge N, Biernat MM, Guidetti A, Abu-Zeinah G, Samarkos M, Anastasopoulou A, de Ramón C, González-López TJ, Hoenigl M, Finizio O, Pinczés LI, Ali N, Vena A, Tascini C, Stojanoski Z, Merelli M, Emarah Z, Kohn M, Barać A, Mladenović M, Mišković B, Ilhan O, Çolak GM, Čerňan M, Gräfe SK, Ammatuna E, Hanakova M, Víšek B, Cabirta A, Nordlander A, Nunes Rodrigues R, Hersby DS, Zambrotta GPM, Wolf D, Núñez-Martín-Buitrago L, Arellano E, Aiello TF, García-Sanz R, Prattes J, Egger M, Limongelli A, Bavastro M, Cvetanoski M, Dibos M, Rasch S, Rahimli L, Cornely OA, and Pagano L
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- Humans, Male, Middle Aged, Female, Aged, Surveys and Questionnaires, Adult, COVID-19 epidemiology, Hematologic Neoplasms complications, Hematologic Neoplasms epidemiology, Critical Illness, Intensive Care Units statistics & numerical data, SARS-CoV-2
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- 2024
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8. Immune-monitoring of myelodysplastic neoplasms: Recommendations from the i4MDS consortium.
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Tentori CA, Zhao LP, Tinterri B, Strange KE, Zoldan K, Dimopoulos K, Feng X, Riva E, Lim B, Simoni Y, Murthy V, Hayes MJ, Poloni A, Padron E, Cardoso BA, Cross M, Winter S, Santaolalla A, Patel BA, Groarke EM, Wiseman DH, Jones K, Jamieson L, Manogaran C, Daver N, Gallur L, Ingram W, Ferrell PB, Sockel K, Dulphy N, Chapuis N, Kubasch AS, Olsnes AM, Kulasekararaj A, De Lavellade H, Kern W, Van Hemelrijck M, Bonnet D, Westers TM, Freeman S, Oelschlaegel U, Valcarcel D, Raddi MG, Grønbæk K, Fontenay M, Loghavi S, Santini V, Almeida AM, Irish JM, Sallman DA, Young NS, van de Loosdrecht AA, Adès L, Della Porta MG, Cargo C, Platzbecker U, and Kordasti S
- Abstract
Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing "immune classes" among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune "risk factors." By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies., Competing Interests: Shahram Kordasti: Novartis: Advisory Board, Speakers bureau, Alexion: Speakers bureau, Beckman Coulter: Speakers bureau, MorphoSys: Research Support (none is related to this publication). Wolfgang Kern declares part‐ownership of MLL Munich Leukemia Laboratory. Austin Kulasekararaj: Research support (to institution): Celgene/BMS and Novartis. Speaker's fees: Alexion/AstraZeneca, Akari, Apellis, Celgene/BMS, Novartis, Pfizer, Ra Pharma/UCB, Roche, SOBI. Scientific advisory board: Alexion/Astra Zeneca, Apellis, Amgen, Agios, Biocryst, Celgene/BMS, Novartis, Pfizer, Regeneron, Roche, SOBI, Janssen, Samsung and Novo Nordisk (none is related to this publication)., (© 2024 The Authors. HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)
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- 2024
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9. Mapping aplastic anaemia hospital activity in England.
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Famokunwa B, Gupta A, Thomas S, Griffin M, and Kulasekararaj A
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Competing Interests: B.F. and A.G. are employees of Pfizer Limited. S.T. is a data analyst employed by Wilmington Healthcare whose work on this project was funded by Pfizer Limited. M.G. has received speaker fees/honoraria from Novartis, Alexion, AstraZeneca, and Sobi. She has contributed to advisory boards for Amgen, Novartis, Sobi, Alexion, AstraZeneca, and Biocryst and provides consultancy to Regeneron and Biocryst. A.K. has received research support for his institution from Celgene/BMS and Novartis. He has acted as a consultant for Samsung, Novo Nordisk, Alexion/AstraZeneca, Arrowhead, and Silence Therapeutics. He has received speaker fees from Alexion/AstraZeneca, Amgen, Celgene/BMS, Pfizer, Novartis, Ra Pharma/UCB, Roche, SOBI, and Janssen. He has contributed to scientific advisory boards and data monitoring committees for Alexion/Astra Zeneca, Apellis, Amgen, Agios, Biocryst, Celgene/BMS, Geron, Novartis, Pfizer, Regeneron, Roche, SOBI, and Janssen.
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- 2024
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10. Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline.
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Kulasekararaj A, Cavenagh J, Dokal I, Foukaneli T, Gandhi S, Garg M, Griffin M, Hillmen P, Ireland R, Killick S, Mansour S, Mufti G, Potter V, Snowden J, Stanworth S, Zuha R, and Marsh J
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- Young Adult, Humans, Aged, Immunosuppressive Agents therapeutic use, Cyclosporine therapeutic use, Bone Marrow Failure Disorders drug therapy, Unrelated Donors, Anemia, Aplastic therapy, Hematopoietic Stem Cell Transplantation, Pancytopenia drug therapy, Hematology
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Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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11. The mortality of COVID-19 in CML patients from 2020 until 2022: results from the EPICOVIDEHA survey.
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El-Ashwah S, Salmanton-García J, Bilgin YM, Itri F, Žák P, Weinbergerová B, Verga L, Omrani AS, Silva MGD, Szotkowski T, Marchetti M, Buquicchio C, Nucci M, Schönlein M, Farina F, Besson C, Prezioso L, Nizamuddin S, Dávila-Valls J, Martín-Pérez S, Bonuomo V, Van Doesum J, Tisi MC, Passamonti F, Méndez GA, Meers S, Maertens J, López-García A, Glenthøj A, Bonnani M, Rinaldi I, Ormazabal-Vélez I, Labrador J, Kulasekararaj A, Espigado I, Demirkan F, De Jonge N, Collins GP, Calbacho M, Blennow O, Al-Khabori M, Adžić-Vukičević T, Arellano E, Mišković B, Mladenović M, Nordlander A, Ráčil Z, Ammatuna E, Cordoba R, Hersby DS, Gräfe S, Emarah Z, Hanakova M, Sacchi MV, Ijaz M, Rahimli L, Nunes Rodrigues R, Zambrotta GPM, Marchesi F, Cornely OA, and Pagano L
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- Humans, Pandemics, Hospitalization, COVID-19, Leukemia, Myelogenous, Chronic, BCR-ABL Positive epidemiology, Hematologic Neoplasms
- Abstract
Since the beginning of the COVID-19 pandemic, there has been an overall improvement in patient mortality. However, haematological malignancy patients continue to experience significant impacts from COVID-19, including high rates of hospitalization, intensive care unit (ICU) admissions, and mortality. In comparison to other haematological malignancy patients, individuals with chronic myeloid leukemia (CML) generally have better prognosis. This study, conducted using a large haematological malignancy patient database (EPICOVIDEHA), demonstrated that the majority of CML patients experienced mild infections. The decline in severe and critical infections over the years can largely be attributed to the widespread administration of vaccinations and the positive response they elicited. Notably, the mortality rate among CML patients was low and exhibited a downward trend in subsequent years. Importantly, our analysis provided confirmation of the effectiveness of vaccinations in CML patients.
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- 2024
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12. Plain language summary of RACE study results: addition of eltrombopag to standard treatment of severe aplastic anemia.
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de Latour RP, Kulasekararaj A, Iacobelli S, Griffin M, Halkes CJ, Dufour C, and Risitano AM
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- Humans, Antilymphocyte Serum therapeutic use, Cyclosporine therapeutic use, Benzoates therapeutic use, Immunosuppressive Agents therapeutic use, Treatment Outcome, Anemia, Aplastic drug therapy
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What Is This Summary About?: Severe aplastic anemia (SAA) and very severe aplastic anemia (vSAA) are blood diseases of the bone marrow. If a suitable donor for bone marrow transplant as initial treatment is unavailable, standard immunosuppression is used. Standard immunosuppression treatment includes horse antithymocyte globulin (hATG) and cyclosporin A (CsA). This summary investigated the results of standard immunosuppression treatment (Group A) versus standard immunosuppression treatment with a medication called eltrombopag (Group B) in participants with SAA and vSAA. Eltrombopag is a medicine that improves the blood platelet level and is taken by mouth (orally)., What Were the Results of the Study?: Compared to Group A, more participants in Group B showed increased blood cell level to a normal range without SAA or vSAA and faster treatment response. Side effects were similar in both groups even with the addition of eltrombopag for Group B. Participants in both groups reported feeling well after 6, 12 and 24 months. Differences in the participant-reported scores (overall health, physical, emotional, and social) between Group A and Group B were minimal., What Do the Results of the Study Mean?: Immunosuppression treatment (hATG plus CsA) with eltrombopag benefited participants with SAA and vSAA and could be the new standard for SAA in persons who cannot undergo bone marrow transplant. At this time, eltrombopag is only approved in specific countries to treat the condition under study that is discussed in this summary. Clinical Trial Registration: NCT02099747 (RACE study).
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- 2024
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13. Diagnosis and investigation of suspected haemophagocytic lymphohistiocytosis in adults: 2023 Hyperinflammation and HLH Across Speciality Collaboration (HiHASC) consensus guideline.
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Cox MF, Mackenzie S, Low R, Brown M, Sanchez E, Carr A, Carpenter B, Bishton M, Duncombe A, Akpabio A, Kulasekararaj A, Sin FE, Jones A, Kavirayani A, Sen ES, Quick V, Dulay GS, Clark S, Bauchmuller K, Tattersall RS, and Manson JJ
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- Adult, Humans, Macrophages, Accidental Falls, Consensus, Ferritins, Lymphohistiocytosis, Hemophagocytic diagnosis
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Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome characterised by persistently activated cytotoxic lymphocytes and macrophages, which, if untreated, leads to multiorgan dysfunction and death. HLH should be considered in any acutely unwell patient not responding to treatment as expected, with prompt assessment to look for what we term the three Fs-fever, falling blood counts, and raised ferritin. Worldwide, awareness of HLH and access to expert management remain inequitable. Terminology is not standardised, classification criteria are validated in specific patient groups only, and some guidelines rely on specialised and somewhat inaccessible tests. The consensus guideline described in this Health Policy was produced by a self-nominated working group from the UK network Hyperinflammation and HLH Across Speciality Collaboration (HiHASC), a multidisciplinary group of clinicians experienced in managing people with HLH. Combining literature review and experience gained from looking after patients with HLH, it provides a practical, structured approach for all health-care teams managing adult (>16 years) patients with possible HLH. The focus is on early recognition and diagnosis of HLH and parallel identification of the underlying cause. To ensure wide applicability, the use of inexpensive, readily available tests is prioritised, but the role of specialist investigations and their interpretation is also addressed., Competing Interests: Declaration of interests AC reports payment or honoraria from CSL, Griffols, Akcea, Biogene, Neurodiem, and Bristol Myers Squibb. AC also reports honoraria from Lupin (£1000) and CSL (£1000) for advisory board participation and support from CSL for attending the Peripheral Nerve Society annual congress, Miami 2022. MBr reports membership of the Medicines and Healthcare products Regulatory Agency Commission of Human Medicines Expert Advisory Group and National Health Service England's Covid medicines Expert Working Group. MBi reports consulting fees from Lilly, Incyte, Roche, and Beigene; and payment or honoraria for lectures, presentations, speaker bureaus, manuscript writing, or educational events from Tevapharma and Celltrion. JJM reports funding from the UCLH Charity Grant funding given to the HLH Service to establish biobank and fund consultant time (£160 000 paid to UCLH). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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- 2024
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14. Haploidentical Transplant with Post-Transplant Cyclophosphamide for Acute Myeloid Leukaemia and Myelodysplastic Syndromes Patients: The Role of Previous Lines of Therapy.
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Avenoso D, Serpenti F, Slonim LB, Bouziana S, Dazzi F, Hannah G, Kenyon M, Mehra V, Kulasekararaj A, Krishamurthy P, Shah MN, Lionel S, Pagliuca A, and Potter V
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Background: Allogeneic haematopoietic stem-cell transplant is an option, potentially curative, for high-risk acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) patients. Post-transplant cyclophosphamide administration allows for the selection of haploidentical donors in patients who are eligible for the procedure but do not have a fully matched donor since it can overcome the HLA barrier. There is still an active debate on whether intensifying the conditioning regimen is necessary with haploidentical donors when peripheral blood stem cells are used as the graft source. Herein, we report our decennial experience of haploidentical stem-cell transplant using peripheral blood stem cells (haplo-PBSC) at King's College Hospital., Objectives: The primary objective was to evaluate overall survival (OS) following haplo-PBSC. Secondary objectives were total OS for patients with less than two previous lines of therapy, OS according to cytomegalovirus (CMV) reactivation, incidence of transplant-related mortality (TRM), graft-versus-host disease (GVHD) and GVHD-relapse-free survival (GRFS)., Results: One-year and three-year total OS were 62% and 43%, respectively, with a median OS of 22 months. One-year and three-year OS for patients with ≤2 and those with >2 previous lines of therapy were 72% and 55%, and 60% and 22%, respectively (p-value=0.04). The median OS in patients with >2 previous and ≤2 lines of therapy was 16 and 49 months, respectively. Cumulative incidence (CI) of relapse was 25% with a median time to relapse of 5 months (range 1 - 38 months)., Conclusions: Haploidentical haematopoietic stem-cell transplant is potentially curative in chemosensitive AML and MDS and offers a high rate of prolonged remission. Our cohort further confirms the role of consolidative haploidentical transplant in patients in complete remission and highlights that patients with heavily pre-treated disease may not benefit from this strategy., Competing Interests: Competing interests: The authors declare no conflict of Interest.
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- 2024
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15. Survival in multiple myeloma and SARS-COV-2 infection through the COVID-19 pandemic: Results from the EPICOVIDEHA registry.
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Musto P, Salmanton-García J, Sgherza N, Bergantim R, Farina F, Glenthøj A, Cengiz Seval G, Weinbergerová B, Bonuomo V, Bilgin YM, van Doesum J, Jaksic O, Víšek B, Falces-Romero I, Marchetti M, Dávila-Valls J, Martín-Pérez S, Nucci M, López-García A, Itri F, Buquicchio C, Verga L, Piukovics K, Navrátil M, Collins GP, Jiménez M, Fracchiolla NS, Labrador J, Prezioso L, Rossi E, Čolović N, Meers S, Kulasekararaj A, Cuccaro A, Blennow O, Valković T, Sili U, Ledoux MP, Batinić J, Passamonti F, Machado M, Duarte RF, Poulsen CB, Méndez GA, Espigado I, Demirkan F, Čerňan M, Cattaneo C, Petzer V, Magliano G, Garcia-Vidal C, El-Ashwah S, Gomes-Da-Silva M, Vena A, Ormazabal-Vélez I, van Praet J, Dargenio M, De-Ramón C, Del Principe MI, Marques-De-Almeida J, Wolf D, Szotkowski T, Obr A, Çolak GM, Nordlander A, Izuzquiza M, Cabirta A, Zambrotta GPM, Cordoba R, Žák P, Ammatuna E, Mayer J, Ilhan O, García-Sanz R, Quattrone M, Arellano E, Nunes-Rodrigues R, Emarah Z, Aiello TF, Hanakova M, Ráčil Z, Bavastro M, Limongelli A, Rahimli L, Marchesi F, Cornely OA, and Pagano L
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- Humans, SARS-CoV-2, Pandemics, Registries, COVID-19, Multiple Myeloma therapy
- Abstract
Patients affected by multiple myeloma (MM) have an increased risk of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection and subsequent coronavirus (20)19 disease (COVID-19)-related death. The changing epidemiological and therapeutic scenarios suggest that there has been an improvement in severity and survival of COVID-19 during the different waves of the pandemic in the general population, but this has not been investigated yet in MM patients. Here we analyzed a large cohort of 1221 patients with MM and confirmed SARS-CoV-2 infection observed between February 2020, and August 2022, in the EPICOVIDEHA registry from 132 centers around the world. Median follow-up was 52 days for the entire cohort and 83 days for survivors. Three-hundred and three patients died (24%) and COVID-19 was the primary reason for death of around 89% of them. Overall survival (OS) was significantly higher in vaccinated patients with both stable and active MM versus unvaccinated, while only a trend favoring vaccinated patients was observed in subjects with responsive MM. Vaccinated patients with at least 2 doses showed a better OS than those with one or no vaccine dose. Overall, according to pandemic waves, mortality rate decreased over time from 34% to 10%. In multivariable analysis, age, renal failure, active disease, hospital, and intensive care unit admission, were independently associated with a higher number of deaths, while a neutrophil count above 0.5 × 10
9 /L was found to be protective. This data suggests that MM patients remain at risk of SARS-CoV-2 infection even in the vaccination era, but their clinical outcome, in terms of OS, has progressively improved throughout the different viral phases of the pandemic., (© 2023 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.)- Published
- 2024
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16. Predictors for improvement in patient-reported outcomes: post hoc analysis of a phase 3 randomized, open-label study of eculizumab and ravulizumab in complement inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria.
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Schrezenmeier H, Kulasekararaj A, Mitchell L, de Latour RP, Devos T, Okamoto S, Wells R, Popoff E, Cheung A, Wang A, Tomazos I, Patel Y, and Lee JW
- Subjects
- Humans, Complement Inactivating Agents therapeutic use, Hemolysis, Fatigue, Quality of Life, Hemoglobinuria, Paroxysmal drug therapy
- Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by uncontrolled terminal complement activation leading to intravascular hemolysis (IVH), thrombosis, and impairments in quality of life (QoL). The aim of this study was to identify the clinical drivers of improvement in patient-reported outcomes (PROs) in patients with PNH receiving the complement component 5 (C5) inhibitors eculizumab and ravulizumab.This post hoc analysis assessed clinical outcomes and PROs from 246 complement inhibitor-naive patients with PNH enrolled in a phase 3 randomized non-inferiority study that compared the C5 inhibitors ravulizumab and eculizumab (study 301; NCT02946463). The variables of interest were lactate dehydrogenase (LDH) levels, a surrogate measure of IVH, and hemoglobin (Hb) levels. PROs were collected using Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) and European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) to assess fatigue and QoL, respectively.Improvements in absolute mean LDH levels were significantly associated with improvements in mean FACIT-F score (p = 0.0024) and EORTC QLQ-C30 global health (GH) score (p < 0.0001) from baseline to day 183. Improvements in scores were achieved despite a non-significant increase in Hb levels. To understand the interaction between LDH and Hb, a regression analysis was performed: LDH response with Hb improvements was a significant predictor of improvement in fatigue. The independent effect of improved Hb did not significantly affect FACIT-F or EORTC QLQ-C30 GH scores.These findings suggest that LDH levels are an important determinant of fatigue and QoL outcomes in patients with PNH. CTR: NCT02946463, October 27, 2016., (© 2023. The Author(s).)
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- 2024
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17. Intravenous ravulizumab in mechanically ventilated patients hospitalised with severe COVID-19: a phase 3, multicentre, open-label, randomised controlled trial.
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Annane D, Pittock SJ, Kulkarni HS, Pickering BW, Khoshnevis MR, Siegel JL, Powell CA, Castro P, Fujii T, Dunn D, Smith K, Mitter S, Kazani S, and Kulasekararaj A
- Subjects
- Male, Adult, Humans, Female, Adolescent, Middle Aged, SARS-CoV-2, Respiration, Artificial, Treatment Outcome, COVID-19, Pneumonia
- Abstract
Background: The complement pathway is a potential target for the treatment of severe COVID-19. We evaluated the safety and efficacy of ravulizumab, a terminal complement C5 inhibitor, in patients hospitalised with severe COVID-19 requiring invasive or non-invasive mechanical ventilation., Methods: This phase 3, multicentre, open-label, randomised controlled trial (ALXN1210-COV-305) enrolled adult patients (aged ≥18 years) from 31 hospitals in France, Japan, Spain, the UK, and the USA. Eligible patients had a confirmed diagnosis of SARS-CoV-2 that required hospitalisation and either invasive or non-invasive mechanical ventilation, with severe pneumonia, acute lung injury, or acute respiratory distress syndrome confirmed by CT scan or x-ray. We randomly assigned participants (2:1) to receive intravenous ravulizumab plus best supportive care (BSC) or BSC alone using a web-based interactive response system. Randomisation was in permuted blocks of six with stratification by intubation status. Bodyweight-based intravenous doses of ravulizumab were administered on days 1, 5, 10, and 15. The primary efficacy endpoint was survival based on all-cause mortality at day 29 in the intention-to-treat (ITT) population. Safety endpoints were analysed in all randomly assigned patients in the ravulizumab plus BSC group who received at least one dose of ravulizumab, and in all randomly assigned patients in the BSC group. The trial is registered with ClinicalTrials.gov, NCT04369469, and was terminated at interim analysis due to futility., Findings: Between May 10, 2020, and Jan 13, 2021, 202 patients were enrolled in the study and randomly assigned to ravulizumab plus BSC or BSC. 201 patients were included in the ITT population (135 in the ravulizumab plus BSC group and 66 in the BSC group). The ravulizumab plus BSC group comprised 96 (71%) men and 39 (29%) women with a mean age of 63·2 years (SD 13·23); the BSC group comprised 43 (65%) men and 23 (35%) women with a mean age of 63·5 years (12·40). Most patients (113 [84%] of 135 in the ravulizumab plus BSC group and 53 [80%] of 66 in the BSC group) were on invasive mechanical ventilation at baseline. Overall survival estimates based on multiple imputation were 58% for patients receiving ravulizumab plus BSC and 60% for patients receiving BSC (Mantel-Haenszel analysis: risk difference -0·0205; 95% CI -0·1703 to 0·1293; one-sided p=0·61). In the safety population, 113 (89%) of 127 patients in the ravulizumab plus BSC group and 56 (84%) of 67 in the BSC group had a treatment-emergent adverse event. Of these events, infections and infestations (73 [57%] vs 24 [36%] patients) and vascular disorders (39 [31%] vs 12 [18%]) were observed more frequently in the ravulizumab plus BSC group than in the BSC group. Five patients had serious adverse events considered to be related to ravulizumab. These events were bacteraemia, thrombocytopenia, oesophageal haemorrhage, cryptococcal pneumonia, and pyrexia (in one patient each)., Interpretation: Addition of ravulizumab to BSC did not improve survival or other secondary outcomes. Safety findings were consistent with the known safety profile of ravulizumab in its approved indications. Despite the lack of efficacy, the study adds value for future research into complement therapeutics in critical illnesses by showing that C5 inhibition can be accomplished in severely ill patients., Funding: Alexion, AstraZeneca Rare Disease., Competing Interests: Declaration of interests DA received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease and is co-inventor on pending patent WO2021211940A1. SJP has received funding for this study, grants or contracts, consulting fees, and honoraria and travel expenses for lectures, advisory boards, and conference attendance from Alexion, AstraZeneca Rare Disease (all paid to institution). SJP also receives royalties from a patent (US-9891219-B). HSK received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease; grants or contracts (paid to institution) from the US National Institutes of Health, the US Department of Defense, the Children's Discovery Institute, and the Longer Life Foundation; consulting fees (personal) from Indemic and Guidepoint; honoraria (personal) from the University of Pittsburgh; support for attending meetings or travel (personal) from the American Thoracic Society; and has participated in an unpaid capacity in advocacy groups, boards, or committees for the American Thoracic Society and the American Society of Clinical Investigation. HSK also has stock in Moderna. BWP received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease; consulting fees (personal) from Philips; and royalties and stock options from Ambient Clinical Analytics, of which he is a member of the board. BWP is also co-inventor on a patent (held by Ambient Clinical Analytics) for the presentation of critical clinical information. MRK received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease. JLS received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease. CAP received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease; and is Chair of the Senhwa Biosciences data safety monitoring board for a COVID-19 clinical trial. PC received funding (paid to institution) for this study, honoraria (personal) for teaching lectures and participation in advisory boards, and payment for expert testimony (personal) from Alexion, AstraZeneca Rare Disease. TF received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease. DD and SK are employees of Alexion, AstraZeneca Rare Disease, own stock in AstraZeneca, and are co-inventors on pending patent WO2021211940A1. KS and SM are employees of Alexion, AstraZeneca Rare Disease and own stock in AstraZeneca. AK received funding (paid to institution) for this study from Alexion, AstraZeneca Rare Disease; consulting fees (personal) from Regeneron, Samsung, Silence Therapeutics, and Novo Nordisk; and honoraria or support for attending meetings or travel (personal) from Alexion, AstraZeneca Rare Disease, Amgen, Sobi, Celgene (a subsidiary of BMS), Biocryst, Pfizer, Roche, Novartis, and Janssen., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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18. Age, successive waves, immunization, and mortality in elderly COVID-19 hematological patients: EPICOVIDEHA findings.
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Rossi G, Salmanton-García J, Cattaneo C, Marchesi F, Dávila-Valls J, Martín-Pérez S, Itri F, López-García A, Glenthøj A, Gomes da Silva M, Besson C, Marchetti M, Weinbergerová B, Jaksic O, Jiménez M, Bilgin YM, Van Doesum J, Farina F, Žák P, Verga L, Collins GP, Bonuomo V, Van Praet J, Nucci M, Meers S, Espigado I, Fracchiolla NS, Valković T, Poulsen CB, Čolović N, Dragonetti G, Ledoux MP, Tascini C, Buquicchio C, Blennow O, Passamonti F, Machado M, Labrador J, Duarte RF, Schönlein M, Prezioso L, Falces-Romero I, Kulasekararaj A, Garcia-Vidal C, Fernández N, Abu-Zeinah G, Ormazabal-Vélez I, Adžić-Vukičević T, Piukovics K, Stoma I, Cuccaro A, Magliano G, Szotkowski T, González-López TJ, El-Ashwah S, Bergantim R, Sili U, Maertens J, Demirkan F, De Ramón C, Petzer V, Del Principe MI, Navrátil M, Dargenio M, Seval GC, Samarkos M, Ráčil Z, Pinczés LI, Lahmer T, Busca A, Méndez GA, Vena A, Biernat MM, Merelli M, Calbacho M, Barać A, Bavastro M, Limongelli A, Ilhan O, Wolf D, Çolak GM, García-Sanz R, Emarah Z, Mišković B, Gräfe SK, Mladenović M, Aiello TF, Núñez-Martín-Buitrago L, Nordlander A, Arellano E, Zambrotta GPM, Ammatuna E, Cabirta A, Sacchi MV, Nunes Rodrigues R, Hersby DS, Hanakova M, Rahimli L, Cordoba R, Cornely OA, and Pagano L
- Subjects
- Aged, Humans, Male, Aged, 80 and over, Female, Vaccination, Immunization, COVID-19, Lymphopenia, Hematologic Neoplasms complications
- Abstract
Objectives: Elderly patients with hematologic malignancies face the highest risk of severe COVID-19 outcomes. The infection's impact on different age groups remains unstudied in detail., Methods: We analyzed elderly patients (age groups: 65-70, 71-75, 76-80, and >80 years old) with hematologic malignancies included in the EPICOVIDEHA registry between January 2020 and July 2022. Univariable and multivariable Cox regression models were conducted to identify factors influencing death in COVID-19 patients with hematological malignancy., Results: The study included data from 3,603 elderly patients (aged 65 or older) with hematological malignancy, with a majority being male (58.1%) and a significant proportion having comorbidities. The patients were divided into four age groups, and the analysis assessed COVID-19 outcomes, vaccination status, and other variables in relation to age and pandemic waves. The 90-day survival rate for patients with COVID-19 was 71.2%, with significant differences between groups. The pandemic waves had varying impacts, with the first wave affecting patients over 80 years old, the second being more severe in 65-70, and the third being the least severe in all age groups. Factors contributing to 90-day mortality included age, comorbidities, lymphopenia, active malignancy, acute leukemia, less than three vaccine doses, severe COVID-19, and using only corticosteroids as treatment., Conclusion: These data underscore the heterogeneity of elderly hematological patients, highlight the different impacts of COVID-19 waves and the pivotal importance of vaccination, and may help in planning future healthcare efforts., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2023
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19. Myeloablative Dose of Busulfan and Fludarabine Combined with In Vivo T Cell Depletion Is Safe and Effective Conditioning for Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients.
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Avenoso D, Mehra V, Slonim LB, de Farias M, Alshehri H, Bouziana S, Krishnamurthy P, Kulasekararaj A, Dazzi F, Wood H, Kenyon M, Leung YT, Anteh S, Shah MN, Hannah G, Serpenti F, Gameil A, Bourlon C, Dragoi OD, Pagliuca A, and Potter V
- Subjects
- Humans, Middle Aged, Busulfan therapeutic use, Recurrence, T-Lymphocytes, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy, Graft vs Host Disease etiology
- Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative strategy for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). The prediction of transplantation-related mortality (TRM) using the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score and an arbitrary upper age limit of 55 years for administering myeloablative conditioning (MAC) are common strategies to ensure a safe procedure. The use of reduced-toxicity conditioning regimens is an additional approach to providing safe and effective myeloablation. Herein we report the outcome of AML and MDS patients conditioned with fludarabine and a myeloablative dose of busulfan (FB4) stratified by age and HCT-CI score. The primary objective was overall survival (OS) for patients age ≥55 years. Secondary objectives were total OS, TRM, graft-versus-host disease (GVHD), and GVHD, relapse-free survival (GRFS). The 2 year OS was 72% in patients age <55 and 51% in patients age ≥55. In patients age ≥55 with an HCT-CI <2, the estimated 2 year OS was 64%, with median OS not reached. In those with HCT-CI ≥2, the 2-year OS was 43%, with a median OS of 14 months. The total cumulative incidence of relapse was 30% regardless of age or HCT-CI score. FB4 conditioning regimen offers a high rate of prolonged remission with a relapse rate similar to that reported in previous studies. These positive outcomes suggest that this conditioning platform can be offered to patients age ≥55 years in the absence of comorbidities, and that age should not be the sole determinant of conditioning intensity., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2023
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20. S56F UBA1 variant is associated with haematological predominant subtype of VEXAS.
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Al-Hakim A, Kulasekararaj A, Norouzi M, Medlock R, Patrick F, Cargo C, and Savic S
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- 2023
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21. Inhibiting C5 in patients with severe COVID-19-the incorrect target? - Authors' reply.
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Annane D, Pittock SJ, Dunn D, and Kulasekararaj A
- Abstract
Competing Interests: DA has received funding, paid to institution, from Alexion, AstraZeneca Rare Disease and is co-inventor on a patent pending (WO2021211940A1). SJP has received funding, paid to institution, from grants; contracts; consulting fees; and honoraria and travel expenses for lectures, advisory boards, and conference attendance from Alexion, AstraZeneca Rare Disease. He receives royalties from a patent (9,891,219B2). DD is an employee of Alexion, AstraZeneca Rare Disease, owns stock in AstraZeneca, and is a co-inventor on a patent pending (WO2021211940A1). AK has received funding, paid to institution, from Alexion, AstraZeneca Rare Disease; consulting fees from Regeneron, Samsung, Silence Therapeutics, and Novo Nordisk; and honoraria and support for attending meetings and travel from Alexion, AstraZeneca Rare Disease, Amgen, Sobi, Celgene, Bristol Myers Squibb, Biocryst, Pfizer, Roche, Novartis, and Janssen.
- Published
- 2023
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22. Convergent somatic evolution commences in utero in a germline ribosomopathy.
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Machado HE, Øbro NF, Williams N, Tan S, Boukerrou AZ, Davies M, Belmonte M, Mitchell E, Baxter EJ, Mende N, Clay A, Ancliff P, Köglmeier J, Killick SB, Kulasekararaj A, Meyer S, Laurenti E, Campbell PJ, Kent DG, Nangalia J, and Warren AJ
- Subjects
- Humans, Young Adult, Adult, Gene Dosage, Hematopoietic Stem Cells, Mutation, Germ Cells, Chromosomes, Human, Pair 7
- Abstract
Clonal tracking of cells using somatic mutations permits exploration of clonal dynamics in human disease. Here, we perform whole genome sequencing of 323 haematopoietic colonies from 10 individuals with the inherited ribosomopathy Shwachman-Diamond syndrome to reconstruct haematopoietic phylogenies. In ~30% of colonies, we identify mutually exclusive mutations in TP53, EIF6, RPL5, RPL22, PRPF8, plus chromosome 7 and 15 aberrations that increase SBDS and EFL1 gene dosage, respectively. Target gene mutations commence in utero, resulting in a profusion of clonal expansions, with only a few haematopoietic stem cell lineages (mean 8, range 1-24) contributing ~50% of haematopoietic colonies across 8 individuals (range 4-100% clonality) by young adulthood. Rapid clonal expansion during disease transformation is associated with biallelic TP53 mutations and increased mutation burden. Our study highlights how convergent somatic mutation of the p53-dependent nucleolar surveillance pathway offsets the deleterious effects of germline ribosomopathy but increases opportunity for TP53-mutated cancer evolution., (© 2023. Springer Nature Limited.)
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- 2023
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23. Impact of SARS-CoV-2 vaccination and monoclonal antibodies on outcome post-CD19-directed CAR T-cell therapy: an EPICOVIDEHA survey.
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van Doesum JA, Salmanton-García J, Marchesi F, Di Blasi R, Falces-Romero I, Cabirta A, Farina F, Besson C, Weinbergerová B, Van Praet J, Schönlein M, López-García A, Lamure S, Guidetti A, De Ramón-Sánchez C, Batinić J, Gavriilaki E, Tragiannidis A, Tisi MC, Plantefeve G, Petzer V, Ormazabal-Vélez I, Marques de Almeida J, Marchetti M, Maertens J, Machado M, Kulasekararaj A, Hernández-Rivas JÁ, Gomes da Silva M, Fernández N, Espigado I, Drgoňa Ľ, Dragonetti G, Metafuni E, Calbacho M, Blennow O, Wolf D, van Anrooij B, Nunes Rodrigues R, Nordlander A, Martín-González JA, Liévin R, Jiménez M, Gräfe SK, García-Sanz R, Córdoba R, Rahimli L, van Meerten T, Cornely OA, and Pagano L
- Subjects
- Humans, COVID-19 Testing, COVID-19 Vaccines, Immunotherapy, Adoptive, Retrospective Studies, SARS-CoV-2, Vaccination, Adaptor Proteins, Signal Transducing, Antibodies, Monoclonal, Antigens, CD19, COVID-19 therapy
- Abstract
Patients with previous CD19-directed chimeric antigen receptor (CAR) T-cell therapy have a prolonged vulnerability to viral infections. Coronavirus disease 2019 (COVID-19) has a great impact and has previously been shown to cause high mortality in this population. Until now, real-world data on the impact of vaccination and treatment on patients with COVID-19 after CD19-directed CAR T-cell therapy are lacking. Therefore, this multicenter, retrospective study was conducted with data from the EPICOVIDEHA survey. Sixty-four patients were identified. The overall mortality caused by COVID-19 was 31%. Patients infected with the Omicron variant had a significantly lower risk of death due to COVID-19 compared with patients infected with previous variants (7% vs 58% [P = .012]). Twenty-six patients were vaccinated at the time of the COVID-19 diagnosis. Two vaccinations showed a marked but unsignificant reduction in the risk of COVID-19-caused mortality (33.3% vs 14.2% [P = .379]). In addition, the course of the disease appears milder with less frequent intensive care unit admissions (39% vs 14% [P = .054]) and a shorter duration of hospitalization (7 vs 27.5 days [P = .022]). Of the available treatment options, only monoclonal antibodies seemed to be effective at reducing mortality from 32% to 0% (P = .036). We conclude that survival rates of CAR T-cell recipients with COVID-19 improved over time and that the combination of prior vaccination and monoclonal antibody treatment significantly reduces their risk of death. This trial was registered at www.clinicaltrials.gov as #NCT04733729., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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24. Biosimilars in rare diseases: a focus on paroxysmal nocturnal hemoglobinuria.
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Kulasekararaj A, Brodsky R, Kulagin A, and Jang JH
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- Humans, Rare Diseases drug therapy, Health Personnel, Drug Approval, Biosimilar Pharmaceuticals therapeutic use, Hemoglobinuria, Paroxysmal drug therapy, Neoplasms drug therapy
- Abstract
Biologics, a class of medicines grown in and purified from genetically engineered cell cultures, have transformed the management of many cancers and rare diseases, such as paroxysmal nocturnal hemoglobinuria. As prescription drug spending has increased and exclusivity periods have expired, manufacturers have developed biosimilars-biologics that may be more affordable and highly similar to a licensed biological therapeutic, with no clinically meaningful differences in terms of safety or efficacy. With biosimilars gaining regulatory approval around the globe and broadening patient access to biologics, this review aims to help rare disease healthcare providers familiarize themselves with biosimilars, understand their development and regulatory approval process, and address practical considerations that may facilitate their use.
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- 2023
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25. Management of patients with germline predisposition to haematological malignancies considered for allogeneic blood and marrow transplantation: Best practice consensus guidelines from the UK Cancer Genetics Group (UKCGG), CanGene-CanVar, NHS England Genomic Laboratory Hub (GLH) Haematological Malignancies Working Group and the British Society of Blood and Marrow Transplantation and cellular therapy (BSBMTCT).
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Clark A, Thomas S, Hamblin A, Talley P, Kulasekararaj A, Grinfeld J, Speight B, Snape K, McVeigh TP, and Snowden JA
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- Humans, Bone Marrow, State Medicine, Genetic Predisposition to Disease, Germ-Line Mutation, Genomics, Transcription Factors genetics, United Kingdom, Hematologic Neoplasms genetics, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Germline predisposition to haematological cancers is increasingly being recognised. Widespread adoption of high-throughput and whole genome sequencing is identifying large numbers of causative germline mutations. Constitutional pathogenic variants in six genes (DEAD-box helicase 41 [DDX41], ETS variant transcription factor 6 [ETV6], CCAAT enhancer binding protein alpha [CEBPA], RUNX family transcription factor 1 [RUNX1], ankyrin repeat domain containing 26 [ANKRD26] and GATA binding protein 2 [GATA2]) are particularly significant in increasing the risk of haematological cancers, with variants in some of these genes also associated with non-malignant syndromic features. Allogeneic blood and marrow transplantation (BMT) is central to management in many haematological cancers. Identification of germline variants may have implications for the patient and potential family donors. Beyond selection of an appropriate haematopoietic stem cell donor there may be sensitive issues surrounding identification and counselling of hitherto asymptomatic relatives. If BMT is needed, there is frequently a clinical urgency that demands a rapid integrated multidisciplinary approach to testing and decision making involving haematologists in collaboration with Clinical and Laboratory Geneticists. Here, we present best practice consensus guidelines arrived at following a meeting convened by the UK Cancer Genetics Group (UKCGG), the Cancer Research UK (CRUK) funded CanGene-CanVar research programme (CGCV), NHS England Genomic Laboratory Hub (GLH) Haematological Oncology Malignancies Working Group and the British Society of Blood and Marrow Transplantation and Cellular Therapy (BSBMTCT)., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2023
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26. Outcome of COVID-19 in allogeneic stem cell transplant recipients: Results from the EPICOVIDEHA registry.
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Busca A, Salmanton-García J, Marchesi F, Farina F, Seval GC, Van Doesum J, De Jonge N, Bahr NC, Maertens J, Meletiadis J, Fracchiolla NS, Weinbergerová B, Verga L, Ráčil Z, Jiménez M, Glenthøj A, Blennow O, Tanase AD, Schönlein M, Prezioso L, Khanna N, Duarte RF, Žák P, Nucci M, Machado M, Kulasekararaj A, Espigado I, De Kort E, Ribera-Santa Susana JM, Marchetti M, Magliano G, Falces-Romero I, Ilhan O, Ammatuna E, Zompi S, Tsirigotis P, Antoniadou A, Zambrotta GPM, Nordlander A, Karlsson LK, Hanakova M, Dragonetti G, Cabirta A, Berg Venemyr C, Gräfe S, Van Praet J, Tragiannidis A, Petzer V, López-García A, Itri F, Groh A, Gavriilaki E, Dargenio M, Rahimli L, Cornely OA, and Pagano L
- Subjects
- Adult, Humans, Middle Aged, Retrospective Studies, Stem Cell Transplantation, COVID-19 etiology, Hematologic Diseases etiology, Hematopoietic Stem Cell Transplantation adverse effects
- Abstract
Background: The outcome of COVID-19 in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is almost uniformely considered poor. The aim of present study was to retrospectively analyse the outcome and risk factors for mortality in a large series of patients who developed COVID-19 infection after an allogeneic HSCT., Methods: This multicenter retrospective study promoted by the European Hematology Association - Infections in Hematology Study Working Group, included 326 adult HSCT patients who had COVID-19 between January 2020 and March 2022., Results: The median time from HSCT to the diagnosis of COVID-19 was 268 days (IQR 86-713; range 0-185 days). COVID-19 severity was mild in 21% of the patients, severe in 39% and critical in 16% of the patients. In multivariable analysis factors associated with a higher risk of mortality were, age above 50 years, presence of 3 or more comorbidities, active hematologic disease at time of COVID-19 infection, development of COVID-19 within 12 months of HSCT, and severe/critical infections. Overall mortality rate was 21% (n=68): COVID-19 was the main or secondary cause of death in 16% of the patients (n=53)., Conclusions: Mortality in HSCT recipients who develop COVID-19 is high and largely dependent on age, comorbidities, active hematologic disease, timing from transplant and severity of the infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Busca, Salmanton-García, Marchesi, Farina, Seval, Van Doesum, De Jonge, Bahr, Maertens, Meletiadis, Fracchiolla, Weinbergerová, Verga, Ráčil, Jiménez, Glenthøj, Blennow, Tanase, Schönlein, Prezioso, Khanna, Duarte, Žák, Nucci, Machado, Kulasekararaj, Espigado, De Kort, Ribera-Santa Susana, Marchetti, Magliano, Falces-Romero, Ilhan, Ammatuna, Zompi, Tsirigotis, Antoniadou, Zambrotta, Nordlander, Karlsson, Hanakova, Dragonetti, Cabirta, Berg Venemyr, Gräfe, Van Praet, Tragiannidis, Petzer, López-García, Itri, Groh, Gavriilaki, Dargenio, Rahimli, Cornely, Pagano and EPICOVIDEHA Consortium.)
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- 2023
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27. COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA).
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Marchesi F, Salmanton-García J, Emarah Z, Piukovics K, Nucci M, López-García A, Ráčil Z, Farina F, Popova M, Zompi S, Audisio E, Ledoux MP, Verga L, Weinbergerová B, Szotkovski T, Da Silva MG, Fracchiolla N, De Jonge N, Collins G, Marchetti M, Magliano G, García-Vidal C, Biernat MM, Van Doesum J, Machado M, Demirkan F, Al-Khabori M, Žák P, Víšek B, Stoma I, Méndez GA, Maertens J, Khanna N, Espigado I, Dragonetti G, Fianchi L, Del Principe MI, Cabirta A, Ormazabal-Vélez I, Jaksic O, Buquicchio C, Bonuomo V, Batinić J, Omrani AS, Lamure S, Finizio O, Fernández N, Falces-Romero I, Blennow O, Bergantim R, Ali N, Win S, Van Praet J, Tisi MC, Shirinova A, Schönlein M, Prattes J, Piedimonte M, Petzer V, Navrátil M, Kulasekararaj A, Jindra P, Sramek J, Glenthøj A, Fazzi R, De Ramón-Sánchez C, Cattaneo C, Calbacho M, Bahr NC, El-Ashwah S, Cordoba R, Hanakova M, Zambrotta G, Sciumè M, Booth S, Rodrigues RN, Sacchi MV, García-Poutón N, Martín-González JA, Khostelidi S, Gräfe S, Rahimli L, Ammatuna E, Busca A, Corradini P, Hoenigl M, Klimko N, Koehler P, Pagliuca A, Passamonti F, Cornely OA, and Pagano L
- Subjects
- Humans, Adult, Follow-Up Studies, COVID-19 Testing, COVID-19, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute drug therapy, Hematology
- Abstract
Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80%; P<0.001). Overall survival in patients with a diagnosis of COVID-19 between January 2020 and August 2020 was significantly lower than that in patients diagnosed between September 2020 and February 2021 and between March 2021 and September 2021 (39.8% vs. 60% vs. 61.9%, respectively; P=0.006). COVID-19 in AML patients was associated with a high mortality rate and modifications of therapeutic algorithms. The best approach to improve survival was to delay AML treatment, whenever possible.
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- 2023
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28. Boosting of Waned Humoral and Cellular Responses to SARS-CoV-2 Variants of Concern Among Patients with Cancer.
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McKenzie DR, Graham R, Lechmere T, Domingo-Vila C, Alaguthurai T, Arman C, Pollock E, Gousis C, Kakkassery H, Carpenter E, Kurshan A, Vidler J, Kulasekararaj A, Patten P, North BV, Tree T, Doores KJ, Hayday AC, and Irshad S
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- Humans, SARS-CoV-2 genetics, COVID-19, Neoplasms, Hematologic Neoplasms
- Abstract
This study offers longitudinal insight into the impact of three SARS-CoV-2 vaccinations on humoral and cellular immunity in patients with solid cancers, patients with hematologic malignancies, and persons without cancer. For all cohorts, virus-neutralizing immunity was significantly depleted over a period of up to 9 months following the second vaccine dose, the one striking exception being IL2 production by SARS-CoV-2 antigen-specific T cells. Immunity was restored by the third vaccine dose, except in a substantial number of patients with hematologic malignancy, for whom both cancer type and treatment schedule were associated with nonresponse. Thus, whereas most patients with myelodysplastic syndrome were conspicuously good responders, some patients with other hematologic malignancies receiving cancer therapies within 2 weeks of vaccination showed no seroconversion despite three vaccine doses. Moreover, SARS-CoV-2 exposure during the course of the study neither prevented immunity waning, even in healthy controls, nor guaranteed vaccine responsiveness. These data offer real-world human immunologic insights that can inform health policy for patients with cancer., Competing Interests: Authors’ Disclosures P. Patten reports grants from Gilead, Roche; personal fees from Janssen, AstraZeneca, Abbvie, Beigene, and Novartis outside the submitted work. A.C. Hayday is co-founder, board member, and equity holder in ImmunoQure AG. This company is interested in antibodies but has no infectious disease or vaccine programs so cannot objectively be in conflict of interest with the work pursued in the study submitted to you; co-founder, board member, and equity holder in Gamma Delta Therapeutics. This company which no longer exists, was interested in gamma delta T cell which are an immunologic components, but the company has no infectious disease or vaccine programs so cannot objectively be in conflict of interest with the work pursued in the study submitted to you; co-founder, board member, and equity holder in Adaptate Biotherapeutics. This company, which no longer exists, was interested in gamma delta T cells which are an immunologic components, but the company has no infectious disease or vaccine programs so cannot objectively be in conflict of interest with the work pursued in the study submitted to you. A.C. Hayday receives research funding from Marengo Inc but this is a T-cell company with no vaccine program. A.C. Hayday receives research funding from Takeda Inc but this is funding solely relates to the use of gamma delta T cells for cancer immunotherapy. No disclosures were reported by the other authors.
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- 2022
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29. Systematic screening and focused evaluation for veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) following allogeneic stem cell transplant is associated with earlier diagnosis and prompt institution of defibrotide treatment.
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Avenoso D, Kenyon M, Mehra V, Krishnamurthy P, Kulasekararaj A, Gandhi S, Dazzi F, Naresh Shah M, Wood H, Leung YT, Eaton A, Anteh S, Cuadrado M, Correia de Farias M, Bourlon C, Dragoi DO, Hardefeldt P, Pagliuca A, and Potter V
- Abstract
Sinusoidal obstructive syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a potentially life-threatening complication following haemopoietic stem cell transplantation (HSCT). The availability of new drugs for malignant hematological conditions has allowed more patients to be eligible for allogeneic haematopoietic stem cell transplants, which has translated into a significant proportion of transplant patients having multiple risk factors for VOD/SOS. Based on these considerations, we undertook a dedicated weekly VOD/SOS ward round, aiming to facilitate early diagnosis of VOD/SOS and pre-emptively identify patients at risk, where a careful evaluation of differential diagnosis is essential. Herein, we present the results of our VOD/SOS ward round; between September 2020 and April 2022, 110 consecutive patients were evaluated in a focused VOD/SOS ward round. From the 110 patients, 108 had undergone HSCT and had at least one known risk factor for developing VOD/SOS. The median number of risk factors present in the VOD/SOS group and non-VOD/SOS group was five (range: three to six) and three (range: zero to seven), respectively. Late-onset VOD/SOS was diagnosed in 45% of our patients. The early identification of patients with multiple risk factors for VOD/SOS allowed an earlier diagnosis and the administration of defibrotide on the same day of diagnosis, which was two days earlier than our previous experience prior to the implementation of this protocol., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Avenoso, Kenyon, Mehra, Krishnamurthy, Kulasekararaj, Gandhi, Dazzi, Naresh Shah, Wood, Leung, Eaton, Anteh, Cuadrado, Correia de Farias, Bourlon, Dragoi, Hardefeldt, Pagliuca and Potter.)
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- 2022
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30. B-cell malignancies treated with targeted drugs and SARS-CoV-2 infection: A European Hematology Association Survey (EPICOVIDEHA).
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Infante MS, Salmanton-García J, Fernández-Cruz A, Marchesi F, Jaksic O, Weinbergerová B, Besson C, Duarte RF, Itri F, Valković T, Szotkovski T, Busca A, Guidetti A, Glenthøj A, Collins GP, Bonuomo V, Sili U, Seval GC, Machado M, Cordoba R, Blennow O, Abu-Zeinah G, Lamure S, Kulasekararaj A, Falces-Romero I, Cattaneo C, Van Doesum J, Piukovics K, Omrani AS, Magliano G, Ledoux MP, de Ramon C, Cabirta A, Verga L, López-García A, Da Silva MG, Stojanoski Z, Meers S, Lahmer T, Martín-Pérez S, Dávila-Vals J, Van Praet J, Samarkos M, Bilgin YM, Karlsson LK, Batinić J, Nordlander A, Schönlein M, Hoenigl M, Ráčil Z, Mladenović M, Hanakova M, Zambrotta GPM, De Jonge N, Adžić-Vukičević T, Nunes-Rodrigues R, Prezioso L, Navrátil M, Marchetti M, Cuccaro A, Calbacho M, Giordano A, Cornely OA, Hernández-Rivas JÁ, and Pagano L
- Abstract
Patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we describe and analyze the outcome of 366 adult patients with chronic lymphocytic leukemia (CLL) or non-Hodgkin Lymphoma (NHL) treated with targeted drugs and laboratory-confirmed COVID-19 diagnosed between February 2020 and January 2022. Median follow-up was 70.5 days (IQR 0-609). Most used targeted drugs were Bruton-kinase inhibitors (BKIs) (N= 201, 55%), anti-CD20 other than rituximab (N=61, 16%), BCL2 inhibitors (N=33, 9%) and lenalidomide (N=28, 8%).Only 16.2% of the patients were vaccinated with 2 or more doses of vaccine at the onset of COVID-19. Mortality was 24% (89/366) on day 30 and 36%(134/366) on the last day of follow-up. Age >75 years (p<0.001, HR 1.036), active malignancy (p<0.001, HR 2.215), severe COVID-19 (p=0.017, HR 2.270) and admission to ICU (p<0.001, HR 5.751) were risk factors for mortality at last day of follow up. There was no difference in OS rates in NHL vs CLL patients (p=0.306), nor in patients treated with or without BKIs (p=0.151). Mortality in ICU was 66% (CLL 61%, NHL 76%). Overall mortality rate decreased according to vaccination status, being 39% in unvaccinated patients, 32% and 26% in those having received one or two doses, respectively, and 20% in patients with a booster dose (p=0.245). Overall mortality rate dropped from 41% during the first semester of 2020 to 25% at the last semester of 2021. These results show increased severity and mortality from COVID-19 in LPDs patients treated with targeted drugs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest of this work., (Copyright © 2022 Infante, Salmanton-García, Fernández-Cruz, Marchesi, Jaksic, Weinbergerová, Besson, Duarte, Itri, Valković, Szotkovski, Busca, Guidetti, Glenthøj, Collins, Bonuomo, Sili, Seval, Machado, Cordoba, Blennow, Abu-Zeinah, Lamure, Kulasekararaj, Falces-Romero, Cattaneo, Van Doesum, Piukovics, Omrani, Magliano, Ledoux, de Ramon, Cabirta, Verga, López-García, Da Silva, Stojanoski, Meers, Lahmer, Martín-Pérez, Dávila-Vals, Van Praet, Samarkos, Bilgin, Karlsson, Batinić, Nordlander, Schönlein, Hoenigl, Ráčil, Mladenović, Hanakova, Zambrotta, De Jonge, Adžić-Vukičević, Nunes-Rodrigues, Prezioso, Navrátil, Marchetti, Cuccaro, Calbacho, Giordano, Cornely, Hernández-Rivas and Pagano.)
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- 2022
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31. The burden of illness of patients with paroxysmal nocturnal haemoglobinuria receiving C5 inhibitors in France, Germany and the United Kingdom: Patient-reported insights on symptoms and quality of life.
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Panse J, Sicre de Fontbrune F, Burmester P, Piggin M, Matos JE, Costantino H, Wilson K, Hakimi Z, Nazir J, Desgraz R, Fishman J, Persson E, and Kulasekararaj A
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- Adult, Cost of Illness, Cross-Sectional Studies, Fatigue drug therapy, Fatigue epidemiology, Fatigue etiology, Germany epidemiology, Humans, Patient Reported Outcome Measures, Quality of Life, Hemoglobinuria, Paroxysmal complications, Hemoglobinuria, Paroxysmal diagnosis, Hemoglobinuria, Paroxysmal drug therapy
- Abstract
Objectives: To assess the clinical, humanistic and economic burden of paroxysmal nocturnal haemoglobinuria (PNH) among C5 inhibitor (C5i)-treated patients with PNH., Methods: This was a web-based, cross-sectional survey (01FEB2021-31MAR2021) of adults with PNH treated with eculizumab (France, Germany, United Kingdom) or ravulizumab (Germany). Self-reported outcomes included: patient characteristics; patient-reported symptoms; and standardised patient-reported outcomes (e.g. Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30])., Results: Among 71 included patients, 98.6% were C5i-treated for ≥3 months (88.7% ≥12 months); among those with self-reported haemoglobin (Hb) levels (n = 63), most (85.7%) were anaemic (defined as ≤12.0 g/dL). Fatigue was the most common symptom at both diagnosis (73.2%) and survey time (63.4%); there were no statistically significant differences in symptom prevalence between treatment subgroups (eculizumab vs. ravulizumab). Total FACIT-Fatigue and EORTC QLQ-C30 scores were substantially lower than European general population references, but there were no statistically significant differences between treatment subgroups. Hb-level subgroups (<10.5 g/dL vs. ≥10.5 d/dL) followed similar trends for all measures, with few significant subgroup differences., Conclusions: Results suggest that there remains a considerable burden and unmet need among C5i-treated patients with PNH that requires improved therapies., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)
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- 2022
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32. Facial lymphoedema, viral warts, and myelodysplastic syndrome: the protean condition of GATA2 deficiency.
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Rudd EC, Kulasekararaj A, and Basu TN
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- Face pathology, GATA2 Transcription Factor genetics, Humans, Papillomaviridae, GATA2 Deficiency, Lymphedema genetics, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes genetics, Warts
- Abstract
Competing Interests: Declaration of interests We declare no competing interests.
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- 2022
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33. COVID-19 and hairy-cell leukemia: an EPICOVIDEHA survey.
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Lamure S, Salmanton-García J, Robin-Marieton E, Jaksic O, Kohn M, Marchesi F, Marchetti M, El-Ashwah S, Demirkan F, Valković T, Fernández N, Tisi MC, Stojanoski Z, Seval GC, Ilhan O, Prezioso L, Merelli M, López-García A, Ledoux MP, Kulasekararaj A, González-López TJ, Gomes da Silva M, Emarah Z, Duarte RF, Cattaneo C, Blennow O, Bilgin YM, Bergantim R, Batinić J, Cordoba R, Essame J, Nordlander A, Nunes Rodrigues R, Sacchi MV, Zompi S, Busca A, Corradini P, Hoenigl M, Klimko N, Koehler P, Pagliuca A, Passamonti F, Duléry R, Cornely OA, Besson C, and Pagano L
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- Humans, COVID-19, Leukemia, Hairy Cell complications, Leukemia, Hairy Cell epidemiology
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- 2022
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34. Composite endpoint to evaluate complement inhibition therapy in patients with paroxysmal nocturnal hemoglobinuria.
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Kulasekararaj A, Glasmacher A, Liu P, Szer J, Araten D, Rauch G, Gwaltney C, Sierra JR, and Lee JW
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- Fatigue, Hemolysis, Humans, Lactate Dehydrogenases, Quality of Life, Hemoglobinuria, Paroxysmal diagnosis, Hemoglobinuria, Paroxysmal drug therapy
- Abstract
This study developed and explored a novel composite endpoint to assess the overall impact that treatment can have on patients living with paroxysmal nocturnal hemoglobinuria (PNH). Candidate composite endpoint variables were selected by a group of experts and included: lactate dehydrogenase levels as a measure of intravascular hemolysis; complete terminal complement inhibition; absence of major adverse vascular events, including thrombosis; absence of any adverse events leading to death or discontinuation of study treatment; transfusion avoidance; and improvements in fatigue-related quality of life as determined by the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. From these variables, a novel composite endpoint was constructed and explored using data collected in the ravulizumab PNH Study 301 (NCT02946463). Thresholds were defined and reported for each candidate variable. Five of the six candidate variables were included in the final composite endpoint; the FACIT-Fatigue score was excluded. Composite endpoint criterion was defined as patients meeting all five selected individual component thresholds. All patients in the ravulizumab arm achieved complete terminal complement inhibition and a reduction in lactate dehydrogenase levels; 51.2% and 41.3% of patients in the ravulizumab arm and eculizumab arm, respectively, achieved all composite endpoint component thresholds (treatment difference: 9.4%; 95% confidence interval: -3.0, 21.5). The composite endpoint provided a single and simultaneous measurement of overall benefit for patients receiving treatment for PNH. Use of the composite endpoint in future PNH research is recommended to determine clinical benefit, and its use in health technology assessments should be evaluated., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)
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- 2022
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35. BNT162b2 COVID-19 and ChAdOx1 nCoV-19 vaccination in patients with myelodysplastic syndromes.
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Abdul-Jawad S, Beatson R, Lechmere T, Graham R, Alaguthurai T, Graham C, Vidler J, Kulasekararaj A, Patten PEM, Doores KJ, and Irshad S
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- BNT162 Vaccine, ChAdOx1 nCoV-19, Humans, Vaccination, COVID-19 prevention & control, Myelodysplastic Syndromes therapy
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- 2022
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36. COVID-19 and CAR T cells: a report on current challenges and future directions from the EPICOVIDEHA survey by EHA-IDWP.
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Busca A, Salmanton-García J, Corradini P, Marchesi F, Cabirta A, Di Blasi R, Dulery R, Lamure S, Farina F, Weinbergerová B, Batinić J, Nordlander A, López-García A, Drgoňa Ľ, Espigado-Tocino I, Falces-Romero I, García-Sanz R, García-Vidal C, Guidetti A, Khanna N, Kulasekararaj A, Maertens J, Hoenigl M, Klimko N, Koehler P, Pagliuca A, Passamonti F, Cornely OA, and Pagano L
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- Humans, Immunotherapy, Adoptive, T-Lymphocytes, COVID-19, Receptors, Chimeric Antigen
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- 2022
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37. Correction to: Special issues related to the diagnosis and management of acquired aplastic anemia in countries with restricted resources, a report on behalf of the Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) Group and Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP of EBMT).
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Iftikhar R, Ahmad P, de Latour R, Dufour C, Risitano A, Chaudhri N, Bazarbachi A, De La Fuente J, Höchsmann B, Osman Ahmed S, Gergis U, Elhaddad A, Halkes C, Albeirouti B, Alotaibi S, Kulasekararaj A, Alzahrani H, Ben Othman T, Cesaro S, Alahmari A, Rihani R, Alshemmari S, Hamidieh AA, Bekadja MA, Passweg J, Al-Khabori M, Rasheed W, Bacigalupo A, Chaudhry QU, Ljungman P, Marsh J, El Fakih R, and Aljurf M
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- 2022
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38. Key findings from the UKCCMP cohort of 877 patients with haematological malignancy and COVID-19: disease control as an important factor relative to recent chemotherapy or anti-CD20 therapy.
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Booth S, Curley HM, Varnai C, Arnold R, Lee LYW, Campton NA, Cook G, Purshouse K, Aries J, Innes A, Cook LB, Tomkins O, Oram HS, Tilby M, Kulasekararaj A, Wrench D, Dolly S, Newsom-Davies T, Pettengell R, Gault A, Moody S, Mittal S, Altohami M, Tillet T, Illingworth J, Mukherjee L, Apperly J, Ashcroft J, Rabin N, Carmichael J, Cazier JB, Kerr R, Middleton G, Collins GP, and Palles C
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- Adult, Antineoplastic Agents, Immunological adverse effects, COVID-19 etiology, COVID-19 immunology, Female, Hematologic Neoplasms immunology, Humans, Leukemia complications, Leukemia drug therapy, Leukemia immunology, Male, Multiple Myeloma complications, Multiple Myeloma drug therapy, Multiple Myeloma immunology, Prospective Studies, Risk Factors, Antigens, CD20 immunology, Antineoplastic Agents, Immunological therapeutic use, COVID-19 complications, Hematologic Neoplasms complications, Hematologic Neoplasms drug therapy
- Abstract
Patients with haematological malignancies have a high risk of severe infection and death from SARS-CoV-2. In this prospective observational study, we investigated the impact of cancer type, disease activity, and treatment in 877 unvaccinated UK patients with SARS-CoV-2 infection and active haematological cancer. The primary end-point was all-cause mortality. In a multivariate analysis adjusted for age, sex and comorbidities, the highest mortality was in patients with acute leukaemia [odds ratio (OR) = 1·73, 95% confidence interval (CI) 1·1-2·72, P = 0·017] and myeloma (OR 1·3, 95% CI 0·96-1·76, P = 0·08). Having uncontrolled cancer (newly diagnosed awaiting treatment as well as relapsed or progressive disease) was associated with increased mortality risk (OR = 2·45, 95% CI 1·09-5·5, P = 0·03), as was receiving second or beyond line of treatment (OR = 1·7, 95% CI 1·08-2·67, P = 0·023). We found no association between recent cytotoxic chemotherapy or anti-CD19/anti-CD20 treatment and increased risk of death within the limitations of the cohort size. Therefore, disease control is an important factor predicting mortality in the context of SARS-CoV-2 infection alongside the possible risks of therapies such as cytotoxic treatment or anti-CD19/anti-CD20 treatments., (© 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2022
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39. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.
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Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, Halkes CJM, Recher C, Barraco F, Forcade E, Vallejo JC, Drexler B, Mear JB, Smith AE, Angelucci E, Raymakers RAP, de Groot MR, Daguindau E, Nur E, Barcellini W, Russell NH, Terriou L, Iori AP, La Rocca U, Sureda A, Sánchez-Ortega I, Xicoy B, Jarque I, Cavenagh J, Sicre de Fontbrune F, Marotta S, Munir T, Tjon JML, Tavitian S, Praire A, Clement L, Rabian F, Marano L, Hill A, Palmisani E, Muus P, Cacace F, Frieri C, van Lint MT, Passweg JR, Marsh JCW, Socié G, Mufti GJ, Dufour C, and Risitano AM
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- Adolescent, Adult, Aged, Aged, 80 and over, Anemia, Aplastic drug therapy, Anemia, Aplastic genetics, Antilymphocyte Serum adverse effects, Benzoates adverse effects, Cyclosporine adverse effects, Drug Therapy, Combination, Female, Humans, Hydrazines adverse effects, Immunosuppressive Agents adverse effects, Male, Middle Aged, Progression-Free Survival, Prospective Studies, Pyrazoles adverse effects, Receptors, Thrombopoietin agonists, Remission Induction, Young Adult, Anemia, Aplastic therapy, Antilymphocyte Serum therapeutic use, Benzoates therapeutic use, Cyclosporine therapeutic use, Hydrazines therapeutic use, Immunosuppression Therapy, Immunosuppressive Agents therapeutic use, Pyrazoles therapeutic use
- Abstract
Background: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia., Methods: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months., Results: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome., Conclusions: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.)., (Copyright © 2022 Massachusetts Medical Society.)
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- 2022
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40. COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA).
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Pagano L, Salmanton-García J, Marchesi F, Busca A, Corradini P, Hoenigl M, Klimko N, Koehler P, Pagliuca A, Passamonti F, Verga L, Víšek B, Ilhan O, Nadali G, Weinbergerová B, Córdoba-Mascuñano R, Marchetti M, Collins GP, Farina F, Cattaneo C, Cabirta A, Gomes-Silva M, Itri F, van Doesum J, Ledoux MP, Čerňan M, Jakšić O, Duarte RF, Magliano G, Omrani AS, Fracchiolla NS, Kulasekararaj A, Valković T, Poulsen CB, Machado M, Glenthøj A, Stoma I, Ráčil Z, Piukovics K, Navrátil M, Emarah Z, Sili U, Maertens J, Blennow O, Bergantim R, García-Vidal C, Prezioso L, Guidetti A, Del Principe MI, Popova M, de Jonge N, Ormazabal-Vélez I, Fernández N, Falces-Romero I, Cuccaro A, Meers S, Buquicchio C, Antić D, Al-Khabori M, García-Sanz R, Biernat MM, Tisi MC, Sal E, Rahimli L, Čolović N, Schönlein M, Calbacho M, Tascini C, Miranda-Castillo C, Khanna N, Méndez GA, Petzer V, Novák J, Besson C, Duléry R, Lamure S, Nucci M, Zambrotta G, Žák P, Seval GC, Bonuomo V, Mayer J, López-García A, Sacchi MV, Booth S, Ciceri F, Oberti M, Salvini M, Izuzquiza M, Nunes-Rodrigues R, Ammatuna E, Obr A, Herbrecht R, Núñez-Martín-Buitrago L, Mancini V, Shwaylia H, Sciumè M, Essame J, Nygaard M, Batinić J, Gonzaga Y, Regalado-Artamendi I, Karlsson LK, Shapetska M, Hanakova M, El-Ashwah S, Borbényi Z, Çolak GM, Nordlander A, Dragonetti G, Maraglino AME, Rinaldi A, De Ramón-Sánchez C, and Cornely OA
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- Adult, Aged, Aged, 80 and over, COVID-19 diagnosis, COVID-19 epidemiology, COVID-19 therapy, Europe epidemiology, Female, Hematologic Neoplasms epidemiology, Hematologic Neoplasms therapy, Hospitalization, Humans, Intensive Care Units, Male, Middle Aged, Registries, Risk Factors, SARS-CoV-2 isolation & purification, Young Adult, COVID-19 complications, Hematologic Neoplasms complications
- Abstract
Background: Patients with hematological malignancies (HM) are at high risk of mortality from SARS-CoV-2 disease 2019 (COVID-19). A better understanding of risk factors for adverse outcomes may improve clinical management in these patients. We therefore studied baseline characteristics of HM patients developing COVID-19 and analyzed predictors of mortality., Methods: The survey was supported by the Scientific Working Group Infection in Hematology of the European Hematology Association (EHA). Eligible for the analysis were adult patients with HM and laboratory-confirmed COVID-19 observed between March and December 2020., Results: The study sample includes 3801 cases, represented by lymphoproliferative (mainly non-Hodgkin lymphoma n = 1084, myeloma n = 684 and chronic lymphoid leukemia n = 474) and myeloproliferative malignancies (mainly acute myeloid leukemia n = 497 and myelodysplastic syndromes n = 279). Severe/critical COVID-19 was observed in 63.8% of patients (n = 2425). Overall, 2778 (73.1%) of the patients were hospitalized, 689 (18.1%) of whom were admitted to intensive care units (ICUs). Overall, 1185 patients (31.2%) died. The primary cause of death was COVID-19 in 688 patients (58.1%), HM in 173 patients (14.6%), and a combination of both COVID-19 and progressing HM in 155 patients (13.1%). Highest mortality was observed in acute myeloid leukemia (199/497, 40%) and myelodysplastic syndromes (118/279, 42.3%). The mortality rate significantly decreased between the first COVID-19 wave (March-May 2020) and the second wave (October-December 2020) (581/1427, 40.7% vs. 439/1773, 24.8%, p value < 0.0001). In the multivariable analysis, age, active malignancy, chronic cardiac disease, liver disease, renal impairment, smoking history, and ICU stay correlated with mortality. Acute myeloid leukemia was a higher mortality risk than lymphoproliferative diseases., Conclusions: This survey confirms that COVID-19 patients with HM are at high risk of lethal complications. However, improved COVID-19 prevention has reduced mortality despite an increase in the number of reported cases., (© 2021. The Author(s).)
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- 2021
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41. Special issues related to the diagnosis and management of acquired aplastic anemia in countries with restricted resources, a report on behalf of the Eastern Mediterranean blood and marrow transplantation (EMBMT) group and severe aplastic anemia working party of the European Society for blood and marrow transplantation (SAAWP of EBMT).
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Iftikhar R, Ahmad P, de Latour R, Dufour C, Risitano A, Chaudhri N, Bazarbachi A, De La Fuente J, Höchsmann B, Osman Ahmed S, Gergis U, Elhaddad A, Halkes C, Albeirouti B, Alotaibi S, Kulasekararaj A, Alzahrani H, Ben Othman T, Cesaro S, Alahmari A, Rihani R, Alshemmari S, Hamidieh AA, Bekadja MA, Passweg J, Al-Khabori M, Rasheed W, Bacigalupo A, Chaudhry QU, Ljungman P, Marsh J, El Fakih R, and Aljurf M
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- Bone Marrow, Bone Marrow Failure Disorders, Bone Marrow Transplantation, Humans, Transplantation Conditioning, Anemia, Aplastic diagnosis, Anemia, Aplastic therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Aplastic anemia is a relatively rare but potentially fatal disorder, with a reported higher incidence in developing countries in comparison to the West. There are significant variations in epidemiological as well as etiological factors of bone marrow failure syndromes in the developing countries in comparison to the developed world. Furthermore, the management of bone marrow failure syndromes in resource constraint settings has significant challenges including delayed diagnosis and referral, limited accessibility to healthcare facilities, treatment modalities as well as limitations related to patients who require allogeneic stem cell transplantation. Here we will provide a review of the available evidence related to specific issues of aplastic anemia in the developing countries and we summarize suggested recommendations from the Eastern Mediterranean blood and bone marrow transplantation (EMBMT) group and the severe aplastic anemia working party of the European Society of blood and marrow transplantation (SAAWP of EBMT) related to the diagnosis and therapeutic options in countries with restricted resources., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2021
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42. Human parainfluenza virus type 3 infections in a haemato-oncology unit: social distancing measures needed in outpatient clinics.
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Anton-Vazquez V, Smith M, Mehra V, Avenoso D, Krishnamurthy P, Kulasekararaj A, Potter V, Pagliuca A, and Zuckerman M
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- Ambulatory Care Facilities, Humans, Male, Middle Aged, Phylogeny, Physical Distancing, Retrospective Studies, Parainfluenza Virus 3, Human genetics, Respirovirus Infections epidemiology
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Background: Human parainfluenza virus type 3 (HPIV3) infections are associated with high mortality in immunocompromised settings, especially in bone marrow transplant recipients. Asymptomatic infection and lack of effective antiviral treatment makes HPIV3 prevention and treatment a real challenge., Aim: To retrospectively investigate the epidemiological characteristics, clinical characteristics and outcomes of 51 haematology patients with confirmed HPIV3 infections, detected between February and May 2019 in the haematology unit at King's College Hospital, London., Methods: Between February and May 2019, HPIV3 RNA was detected in combined nose and throat swab samples collected from 51 symptomatic haematology patients, 41 of whom attended the haematology outpatient unit. Clinical data were reviewed retrospectively and a timeline of patients' appointments drawn up to investigate transmission. Sequencing analysis was performed on 14 stored samples., Findings: Fifty-one patients were identified with HPIV3 infection. Mean age was 54 years (SD: 12; range: 19-72) and 60% (31/51) were male. There were 41 (80%) bone marrow transplant recipients, 24 had an allograft, and 17 an autograft. Thirty-day and 3-month mortality post HPIV3 was 6% and 14%, respectively. Lower respiratory tract infection and inpatient acquisition were associated with higher mortality (6/7 vs 1/7, P = 0.010; and 5/7 vs 2/7, P = 0.031). Onset of HPIV3 infection in patients within 6 days of attending the clinic was associated with the clusters identified in phylogenetic analysis (64% (9/14) vs 21% (8/37); odds ratio: 6.5 (confidence interval: 95% 1.7-25); P = 0.006)., Conclusion: Timelines suggested community transmission, but also possible transmission patterns within the outpatients and subsequent nosocomial transmission within the same ward. Early recognition of HPIV3 infection and the use of polymerase chain reaction and sequence analysis is fundamental in identifying respiratory virus outbreaks and person-to-person transmission. Careful planning of outpatient clinic attendance is required to minimize contact and prevent respiratory virus transmission in immunosuppressed patients., (Copyright © 2021 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.)
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- 2021
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43. Risk of COVID-19 death in cancer patients: an analysis from Guy's Cancer Centre and King's College Hospital in London.
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Russell B, Moss CL, Shah V, Ko TK, Palmer K, Sylva R, George G, Monroy-Iglesias MJ, Patten P, Ceesay MM, Benjamin R, Potter V, Pagliuca A, Papa S, Irshad S, Ross P, Spicer J, Kordasti S, Crawley D, Wylie H, Cahill F, Haire A, Zaki K, Sita-Lumsden A, Josephs D, Enting D, Swampillai A, Sawyer E, D'Souza A, Gomberg S, Harrison C, Fields P, Wrench D, Rigg A, Sullivan R, Kulasekararaj A, Dolly S, and Van Hemelrijck M
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- Adult, Aged, Aged, 80 and over, COVID-19 complications, COVID-19 pathology, COVID-19 virology, Female, Hematologic Neoplasms complications, Hematologic Neoplasms pathology, Hematologic Neoplasms virology, Hospitals, Humans, London epidemiology, Male, Middle Aged, Neoplasms complications, Neoplasms pathology, Neoplasms virology, Risk Factors, COVID-19 epidemiology, Hematologic Neoplasms epidemiology, Neoplasms epidemiology, SARS-CoV-2 pathogenicity
- Abstract
Background: Using an updated dataset with more patients and extended follow-up, we further established cancer patient characteristics associated with COVID-19 death., Methods: Data on all cancer patients with a positive reverse transcription-polymerase chain reaction swab for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) at Guy's Cancer Centre and King's College Hospital between 29 February and 31 July 2020 was used. Cox proportional hazards regression was performed to identify which factors were associated with COVID-19 mortality., Results: Three hundred and six SARS-CoV-2-positive cancer patients were included. Seventy-one had mild/moderate and 29% had severe COVID-19. Seventy-two patients died of COVID-19 (24%), of whom 35 died <7 days. Male sex [hazard ratio (HR): 1.97 (95% confidence interval (CI): 1.15-3.38)], Asian ethnicity [3.42 (1. 59-7.35)], haematological cancer [2.03 (1.16-3.56)] and a cancer diagnosis for >2-5 years [2.81 (1.41-5.59)] or ≥5 years were associated with an increased mortality. Age >60 years and raised C-reactive protein (CRP) were also associated with COVID-19 death. Haematological cancer, a longer-established cancer diagnosis, dyspnoea at diagnosis and raised CRP were indicative of early COVID-19-related death in cancer patients (<7 days from diagnosis)., Conclusions: Findings further substantiate evidence for increased risk of COVID-19 mortality for male and Asian cancer patients, and those with haematological malignancies or a cancer diagnosis >2 years. These factors should be accounted for when making clinical decisions for cancer patients., (© 2021. The Author(s).)
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- 2021
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44. Mixed T cell lineage chimerism in acute leukemia/MDS using pre-emptive donor lymphocyte infusion strategy-Is it prognostic?-a single-center retrospective study.
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Sheth V, Potter V, de Lavallade H, Gandhi S, Kulasekararaj A, Krishnamurthy P, Mehra V, Dazzi F, Mufti G, Pagliuca A, Mclornan D, and Raj K
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- Chimerism, Female, Graft vs Host Disease etiology, Graft vs Host Disease genetics, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes genetics, Prognosis, Retrospective Studies, Survival Analysis, Transplantation, Homologous, Unrelated Donors, Leukemia, Myeloid, Acute therapy, Lymphocyte Transfusion, Myelodysplastic Syndromes therapy
- Abstract
Pre-emptive DLI (pDLI) is an effective strategy in lowering the risk of relapse without significantly increasing the risk of graft-versus-host disease (GVHD) in the case of T cell lineage mixed chimerism (MC) post allogeneic transplant in hematological malignancies. Many patients, however, fail to receive timely pDLI and have dismal outcomes, which are not taken into consideration. We compared long-term outcomes of 106 patients having T cell MC after day 60 and undergoing allogeneic stem cell allograft for acute leukemia from an unrelated donor (UD), with 111 patients having complete chimerism (CC). Fifty-three (56%) patients received prophylactic pDLI. Thirty-six patients (67%) had a response (RR), 17 (33%) had no response (NR), and fifty-two (54%) did not receive any pDLI (ND). OS was better in MC group as compared to CC (54% vs 43%, p = 0.04), mainly due to reduction in NRM (14% vs 25%, p = 0.05), and all grade acute and chronic GVHD. Within the MC group, response to pDLI was the only significant factor predicting OS, DFS, and relapses with NR and ND having unfavorable outcomes as compared to RR (p = 0.001). T cell MC in patients undergoing UD allografts with alemtuzumab is no longer an adverse prognostic factor, as compared to patients having CC, after timely implementation of pDLI., (© 2021. The Author(s).)
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- 2021
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45. British Society for Haematology guidelines for the management of adult myelodysplastic syndromes.
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Killick SB, Ingram W, Culligan D, Enright H, Kell J, Payne EM, Krishnamurthy P, Kulasekararaj A, Raghavan M, Stanworth SJ, Green S, Mufti G, Quek L, Cargo C, Jones GL, Mills J, Sternberg A, Wiseman DH, and Bowen D
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- Adult, Humans, Anemia complications, Anemia therapy, Antineoplastic Agents therapeutic use, Azacitidine therapeutic use, Blood Transfusion methods, Decitabine therapeutic use, Disease Management, Hematinics therapeutic use, Hematopoietic Stem Cell Transplantation methods, Hemorrhage complications, Hemorrhage therapy, Iron Chelating Agents therapeutic use, Neutropenia complications, Neutropenia therapy, Thrombocytopenia complications, Thrombocytopenia therapy, Myelodysplastic Syndromes complications, Myelodysplastic Syndromes therapy
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- 2021
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46. British Society for Haematology guidelines for the diagnosis and evaluation of prognosis of Adult Myelodysplastic Syndromes.
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Killick SB, Wiseman DH, Quek L, Cargo C, Culligan D, Enright H, Green S, Ingram W, Jones GL, Kell J, Krishnamurthy P, Kulasekararaj A, Mills J, Mufti G, Payne EM, Raghavan M, Stanworth SJ, Sternberg A, and Bowen D
- Subjects
- Adult, Humans, Clonal Hematopoiesis, Cytogenetic Analysis, Flow Cytometry, Genetic Predisposition to Disease, Germ-Line Mutation, Prognosis, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes genetics
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- 2021
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47. The clinical and histopathological spectrum of neutrophilic inflammatory disease encountered in the setting of myelodysplastic syndrome.
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Maguire CA, Kulasekararaj AG, Salisbury JR, Walsh SA, Mufti GJ, and du Vivier AWP
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- Female, Humans, Middle Aged, Neutrophils, Inflammation etiology, Inflammation pathology, Myelodysplastic Syndromes complications
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- 2021
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48. Early and late-onset veno-occlusive disease/sinusoidal syndrome post allogeneic stem cell transplantation - a real-world UK experience.
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Mehra V, Tetlow S, Choy A, de Lavallade H, Kulasekararaj A, Krishnamurthy P, Avenoso D, Marsh J, Potter V, Mufti G, Pagliuca A, and Gandhi S
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- Adult, Humans, Polydeoxyribonucleotides, United Kingdom, Hematologic Neoplasms, Hematopoietic Stem Cell Transplantation adverse effects, Hepatic Veno-Occlusive Disease diagnosis, Hepatic Veno-Occlusive Disease drug therapy, Hepatic Veno-Occlusive Disease etiology
- Abstract
Classical veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication post allogeneic hematopoietic stem cell transplantation (HSCT). Before the recently revised EBMT criteria, the Baltimore and modified Seattle criteria failed to recognize the syndrome of late-onset VOD. We present real-world experience from a large UK transplant center reporting on VOD/SOS in consecutive HSCT adult patients (n = 530), transplanted for hematological cancers. We identified 27 patients treated with Defibrotide for VOD/SOS diagnosis, where detailed data were available for final analysis. Using standard definitions including EBMT criteria, around 30% (n = 8/27) of cases classified as late-onset VOD presenting at median of 46 (22-93) days but with D100 survival (63% vs 58%, Log-rank; P = 0.81) comparable to classical VOD. Hazard ratio for D100 mortality was 2.82 (95% CI: 1.74-4.56, P < .001, Gray test) with all VOD/SOS events. Twenty percent (n = 2/8) of late-onset VOD patients were anicteric and 42% (n = 8) classical VOD patients presented with refractory thrombocytopenia, while less than half met EBMT criteria for classical VOD in adults, highlighting gaps in real-world diagnostic limitations using EBMT criteria. However, challenges remain about underrecognition and difficulties related to early defibrotide access for treatment of late-onset VOD in current treatment guidelines. Our report strongly supports early Defibrotide for the treatment of severe VOD/SOS in adults regardless of time of onset., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)
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- 2021
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49. One-year efficacy and safety of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria naïve to complement inhibitor therapy: open-label extension of a randomized study.
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Schrezenmeier H, Kulasekararaj A, Mitchell L, Sicre de Fontbrune F, Devos T, Okamoto S, Wells R, Rottinghaus ST, Liu P, Ortiz S, Lee JW, and Socié G
- Abstract
Background: Ravulizumab, the only long-acting complement C5 inhibitor for adults with paroxysmal nocturnal hemoglobinuria (PNH), demonstrated non-inferiority to eculizumab after 26 weeks of treatment in complement inhibitor-naïve patients during a phase III randomized controlled trial. We present open-label extension results with up to 52 weeks of treatment., Methods: Patients assigned to ravulizumab every 8 weeks (q8w) or eculizumab every 2 weeks during the randomized primary evaluation period received ravulizumab q8w during the 26-week extension. Efficacy endpoints were lactate dehydrogenase (LDH) normalization, transfusion avoidance, breakthrough hemolysis (BTH), LDH levels, Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale, and stabilized hemoglobin. Serum free C5 levels and safety were assessed. Outcomes as of the data cut-off (4 September 2018) were summarized using descriptive statistics., Results: Overall, 124 patients continued ravulizumab, and 119 switched from eculizumab to ravulizumab. During the extension, 43.5% and 40.3% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved LDH normalization; 76.6% and 67.2% avoided transfusion. BTH decreased in the eculizumab-ravulizumab arm; no events were associated with free C5 ⩾0.5 μg/mL while receiving ravulizumab. Overall, 73.4% and 65.5% of patients in the ravulizumab-ravulizumab and eculizumab-ravulizumab arms, respectively, achieved stabilized hemoglobin. Similar proportions of patients achieved ⩾3-point improvement in FACIT-Fatigue at week 52 (ravulizumab-ravulizumab, 64.5%; eculizumab-ravulizumab, 57.1%). All patients maintained free C5 <0.5 μg/mL during the ravulizumab extension, including those who experienced C5 excursions ⩾0.5 μg/mL while receiving eculizumab during the primary evaluation period. Adverse events were comparable between groups and decreased over time., Conclusion: In adult, complement inhibitor-naïve patients with PNH, ravulizumab q8w for up to 52 weeks demonstrated durable efficacy and was well tolerated, with complete and sustained free C5 inhibition and a decreased incidence of BTH with no events associated with loss of free C5 control., Trial Registration: ClinicalTrials.gov identifier, NCT02946463., Competing Interests: Conflict of interest statement: Hubert Schrezenmeier: Honoraria and grants (to the University Hospital of Ulm) from Alexion Pharmaceuticals, Inc.; grants (to the University Hospital of Ulm) from Apellis, Ra Pharmaceuticals, and Sanofi; grants and other support (to the University Hospital of Ulm) from Roche; patent pending (PCT/EP2017/065979). Austin Kulasekararaj: Travel grants from Achillion, Alexion Pharmaceuticals, Inc., Celgene, and Ra Pharmaceuticals; advisory board fees (honoraria) from Alexion Pharmaceuticals, Inc., Celgene, Novartis, Ra Pharmaceuticals, and Regeneron. Lindsay Mitchell: Honoraria from Alexion Pharmaceuticals, Inc. Flore Sicre de Fontbrune: Honoraria and grants (to St. Louis Hospital) from Alexion Pharmaceuticals, Inc. Timothy Devos: Consulting fees from Novartis, Alexion Pharmaceuticals, Inc., and Celgene. Shinichiro Okamoto: Grants and personal fees from Alexion Pharmaceuticals, Inc., Astellas, Chugai, Daiichi Sankyo, JCR Pharma, Mochida, Novartis, Pfizer, and Takeda; grants from Asahi Kasei Pharma, Dainihon Sumitomo, Shionogi, and Teijin Pharma; and personal fees from Bristol-Meyers Squibb and Nihon Shinyaku. Richard Wells: Honoraria and consulting fees from Alexion Pharmaceuticals, Inc. Scott T. Rottinghaus: Employee and stockholder of Alexion Pharmaceuticals, Inc.; patent for “Dosage and administration of anti-c5 antibodies for treatment of paroxysmal nocturnal hemoglobinuria (pnh) and atypical hemolytic uremic syndrome (ahus).” Peng Liu, Stephan Ortiz: Employees and stockholders of Alexion Pharmaceuticals, Inc. Jong Wook Lee: Honoraria, consulting fees, and grants (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals, Inc. Gérard Socié: Speaker fees and grants from, and a consultant for, Alexion Pharmaceuticals, Inc., (© The Author(s), 2020.)
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- 2020
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50. Small Paroxysmal Nocturnal Hemoglobinuria Clones in Autoimmune Hemolytic Anemia: Clinical Implications and Different Cytokine Patterns in Positive and Negative Patients.
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Fattizzo B, Giannotta J, Zaninoni A, Kulasekararaj A, Cro L, and Barcellini W
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- Adolescent, Adult, Aged, Aged, 80 and over, Anemia, Hemolytic, Autoimmune epidemiology, Autoantibodies metabolism, Child, Child, Preschool, Clone Cells, Cytokines metabolism, Cytotoxicity, Immunologic, Female, Hemoglobinuria, Paroxysmal epidemiology, Hemolysis, Humans, Italy epidemiology, Male, Middle Aged, Risk, Thrombosis epidemiology, Young Adult, Anemia, Hemolytic, Autoimmune immunology, Bone Marrow pathology, Erythrocytes pathology, Hemoglobinuria, Paroxysmal immunology
- Abstract
Autoimmune hemolytic anemia (AIHA) is characterized by immune mediated erythrocytes destruction by autoantibodies with or without complement activation. Additional pathologic mechanisms include cellular cytotoxicity, cytokline dysregulation, and inadequate bone marrow compensation with fibrosis/dyserythropoiesis. The latter resembles that of bone marrow failures, namely aplastic anemia and myelodysplastic syndromes. Paroxysmal nocturnal hemoglobinuria (PNH) clones are increasingly recognized in bone marrow failure syndromes, and their selection and expansion are thought to be mediated by immune mechanisms. In this study, we aimed to evaluate the prevalence of PNH clones in 99 patients with primary AIHA, and their correlations with disease features and outcomes. Moreover, in the attempt to disclose the physiopathology of PNH positivity in AIHA, serum levels of several immunomodulatory cytokines were tested. A PNH clone was found in 37 AIHA patients (37,4%), with a median size of 0.2% on granulocytes (range 0.03-85). Two patients showed a large clone (16 and 85%) and were therefore considered as AIHA/PNH association and not included in further analysis. Compared to PNH negative, PNH positive cases displayed a higher hemolytic pattern with adequate bone marrow compensation. AIHA type, response to therapy, complications and outcome were comparable between the two groups. Regarding cytokine levels, IFN-γ and IL-17 were lower in PNH positive vs. PNH negative AIHAs (0.3 ± 0.2 vs. 1.33 ± 2.5; 0.15 ± 0.3 vs. 3,7 ± 9.1, respectively, p = 0.07 for both). In PNH positive AIHAs, IFN-γ positively correlated with reticulocytes ( r = 0.52, p = 0.01) and with the bone marrow responsiveness index ( r = 0.69, p = 0.002). Conversely, IL-6 and IL-10 showed the same pattern in PNH positive and PNH negative AIHAs. IL-6 levels and TGF-β positively correlated with clone size ( r = 0.35, p = 0.007, and r = 0.38, p = 0.05, respectively), as well as with LDH values ( r = 0.69, p = 0.0003, and r = 0.34, p = 0.07, respectively). These data suggest testing PNH clones in AIHA since their prevalence is not negligible, and may correlate with a prominent hemolytic pattern, a higher thrombotic risk, and a different therapy indication. PNH testing is particularly advisable in complex cases with inadequate response to AIHA-specific therapy. Cytokine patterns of PNH positive and negative AIHAs may give hints about the pathogenesis of highly hemolytic AIHA., (Copyright © 2020 Fattizzo, Giannotta, Zaninoni, Kulasekararaj, Cro and Barcellini.)
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- 2020
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