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Zhao XL, Zhang LN, Zhang XY, Hao MZ, Chen SL, Wei JL, He Y, Han MZ, Jiang EL. [Clinical observation of allogeneic hematopoietic stem cell transplantation for treating five cases of classic paroxysmal nocturnal hemoglobinuria]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2024; 45:1125-1128. [PMID: 39765354 PMCID: PMC11886705 DOI: 10.3760/cma.cn121090-20240612-00221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Indexed: 03/09/2025]
Abstract
This study enrolled five patients with classic paroxysmal nocturnal hemoglobinuria (cPNH) who underwent allogeneic hematopoietic stem cell transplantation in our hospital from 2019 to 2023. All five patients were male, with a median age of 26 (range: 26-46) years. The median time from diagnosis to allo-HSCT was 5.5 (range: 3.6-18.0) years. The median PNH granulocyte clone size was 96.3% (ranged 90.0%-99.7%), and the median lactate dehydrogenase (LDH) level was 2 224 IU/L (8896-fold of the upper limit of normal). All patients were detected to have bone marrow hyperplasia by trephine biopsy. The stem cell source came from four haploidentical donors and one HLA-identical sibling donor. Among the five patients, three underwent myeloablative conditioning (MAC) and two underwent reduced-intensity conditioning (RIC) treatment. None of the patients experienced primary implantation failure. The neutrophil implantation time was 15 (range: 13-21) days, and the platelet implantation time was 24 (range: 13-60) days. The three patients developed grade II acute graft-versus-host disease (aGVHD). No patients developed grade Ⅲ/Ⅳ aGVHD. The two patients developed localized chronic GVHD (cGVHD), and no patients developed extensive cGVHD. PNH clones turned negative in all patients after 2 (range: 1-3) months of transplantation. At a median follow-up of 16 (range: 6-34) months, one patient died of relapse and infection, and the remaining four patients survived, of which two patients had discontinued all drugs.
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Affiliation(s)
- X L Zhao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China
| | - L N Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China
| | - X Y Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China
| | - M Z Hao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China
| | - S L Chen
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China
| | - J L Wei
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China
| | - Y He
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China
| | - M Z Han
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China
| | - E L Jiang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China Tianjin Institutes of Health Science, Tianjin 301600, China
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Rich C, Wilson K, Olsen J, Pedersen M, Frederiksen H. The disease burden of paroxysmal nocturnal hemoglobinuria in Denmark: Epidemiology, survival, healthcare resource utilization, costs, treatment gaps, and labor market attachment. Eur J Haematol 2024; 112:412-423. [PMID: 38009907 DOI: 10.1111/ejh.14128] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 10/13/2023] [Accepted: 10/16/2023] [Indexed: 11/29/2023]
Abstract
OBJECTIVES To establish epidemiology, healthcare costs, and labor market attachment in patients with paroxysmal nocturnal hemoglobinuria (Pt-PNH) in Denmark. METHODS Data were from Statistics Denmark and the Danish Health Data Authority national population registers (2005-2021). Descriptive baseline statistics characterized the Pt-PNH analytic population; ordinary least squares and adjusted Cox proportional hazards regressions measured outcomes in the Pt-PNH versus Danish general population matched comparators. RESULTS Overall PNH incidence in Denmark was n = 11 during 2007-2009, n = 25 during 2016-2018 and n = 7 during 2019-2020; prevalence increased from n = 13 in 2006 to n = 62 in 2021. Of the overall n = 85 Pt-PNH; n = 24 were treated with complement-5 inhibitors (Pt-C5i) and n = 61 not treated with C5i (Pt-nC5i). Versus respective comparators, all patients had significantly greater annual per-patient costs (from inpatient hospital admissions, outpatient contacts, PNH treatments; indirect costs from lost earnings + transfer payments; post-diagnosis for Pt-PNH and Pt-nC5i, post-treatment initiation for Pt-C5i). The Pt-C5i incurred the greatest healthcare and indirect cost differences (€709 119; €152 832, respectively) followed by the Pt-PNH (€189 323; €29 159, respectively) and Pt-nC5i (€95 548; €4713, respectively). The Pt-PNH versus comparators also had an increased hazard of death (2.71 [95% CI, 1.63 - 4.51]). CONCLUSION Although a rare disease, PNH is associated with significant patient, healthcare system, and societal burdens in Denmark.
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Affiliation(s)
- Carly Rich
- Swedish Orphan Biovitrum AB, Stockholm, Sweden
| | - Koo Wilson
- Swedish Orphan Biovitrum AB, Stockholm, Sweden
| | | | | | - Henrik Frederiksen
- Department and Research Unit of Haematology, Odense University Hospital and Department of Clinical Research, University of Southern Denmark, Odense, Denmark
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Lee J, Lee H, Kim S, Suh HS. Efficacy of complement inhibitors for patients with paroxysmal nocturnal hemoglobinuria: a systematic review and meta-analysis. Ther Adv Hematol 2023; 14:20406207231216080. [PMID: 38105771 PMCID: PMC10725119 DOI: 10.1177/20406207231216080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 10/19/2023] [Indexed: 12/19/2023] Open
Abstract
Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematological disease. The development of complement inhibitors such as eculizumab, ravulizumab, and pegcetacoplan has revolutionized the management of PNH, leading to improvements in overall survival and quality of life for patients. Objectives This systematic review aims to provide comprehensive evidence of the efficacy of complement inhibitors in relation to treatment duration. Design This is a systematic review and meta-analysis. Data sources and methods A thorough literature search was conducted in MEDLINE, EMBASE, and the Cochrane Library up to 3 May 2022. We included all prospective interventional studies including single-arm trials. The primary outcomes of interest were lactate dehydrogenase (LDH) levels, hemoglobin (Hb) concentrations, transfusion avoidance, and Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) scores. Results Our study included a total of 27 studies, comprising 5 randomized controlled trials and 11 single-arm trials, with a total of 912 patients with PNH. We stratified the studies according to treatment duration, based on the most frequently reported period of 26 weeks. Our analysis showed that treatment-naïve patients who received complement inhibitors had a pooled estimate of a decrease in LDH levels from baseline by -1462.0 U/L (95% CI: -1735.6 to -1188.5) for treatment ⩽26 weeks and -1696.5 U/L (95% CI: -2122.7 to -1270.2) for treatment >26 weeks. The mean Hb levels were increased by 1.4 g/dL (95% CI: 0.5-2.3) and 1.9 g/dL (95% CI: 0.7-3.1) in each group. Treatment with any complement inhibitor prevented the need for transfusion in at least 50% of patients with PNH in all treatment periods. Clinically meaningful improvements in FACIT-F were observed both before and after 26 weeks, with a pooled estimate of 6.8 (95% CI: 6.0-7.6) and 9.5 (95% CI: 7.0-12.0), respectively. Conclusion Our findings suggest that complement inhibitors can result in positive treatment outcomes and sustained benefits for patients with PNH.
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Affiliation(s)
- Jiyeon Lee
- Department of Regulatory Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Institute of Regulatory Innovation Through Science, Kyung Hee University, Seoul, Republic of Korea
| | - Haeseon Lee
- Department of Regulatory Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Institute of Regulatory Innovation Through Science, Kyung Hee University, Seoul, Republic of Korea
| | - Siin Kim
- College of Pharmacy, Woosuk University, Wanju-gun, Republic of Korea
| | - Hae Sun Suh
- Department of Regulatory Science, Graduate School, Kyung Hee University, Seoul, Republic of Korea
- Institute of Regulatory Innovation Through Science, Kyung Hee University, Seoul, Republic of Korea
- College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Republic of Korea
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Fishman J, Wilson K, Drzewiecka A, Pochopień M, Dingli D. The cost-effectiveness of pegcetacoplan in complement treatment-naïve adults with paroxysmal nocturnal hemoglobinuria in the USA. J Comp Eff Res 2023; 12:e230055. [PMID: 37655691 PMCID: PMC10690430 DOI: 10.57264/cer-2023-0055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Accepted: 08/09/2023] [Indexed: 09/02/2023] Open
Abstract
Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia, bone marrow failure and thrombosis, and is associated with high healthcare burden. We evaluated the cost-effectiveness of pegcetacoplan, a proximal complement-3 inhibitor (C3i), compared with the C5i, eculizumab and ravulizumab, in complement treatment-naive adults with PNH, from the US healthcare payer perspective. Materials & methods: A de novo cost-effectiveness model based on a Markov cohort structure evaluated lifetime (55-year) PNH costs and outcomes. The 6-month cycles of the model reflected the follow-up period of PRINCE (NCT04085601), an open-label trial of pegcetacoplan compared with eculizumab in C5i-naive patients. Data from PRINCE informed the clinical, safety and health-related quality of life outcomes in the model. Results: Pegcetacoplan was associated with lifetime cost savings of USD1,176,808 and USD213,062 relative to eculizumab and ravulizumab, respectively (largely attributed to reduced drug costs and blood transfusions), and additional quality-adjusted life years (QALYs) of 0.25 and 0.24. Conclusion: In patients with PNH who are treatment-naive, the base-case cost-effectiveness analysis, scenario analysis and sensitivity analysis showed both lifetime cost savings and increased QALYs associated with pegcetacoplan compared with eculizumab or ravulizumab in the USA.
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Affiliation(s)
| | - Koo Wilson
- Swedish Orphan Biovitrum AB, Stockholm, Sweden
| | - Aleksandra Drzewiecka
- Putnam PHMR, Krakow, Poland (previously Creativ-Ceutical, Krakow, Poland during conduct of study)
| | - Michał Pochopień
- Assignity, Krakow, Poland (previously of Creativ-Ceutical, Krakow, Poland during conduct of study)
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Hakimi Z, Wilson K, McAughey E, Pochopien M, Wojciechowski P, Toumi M, Knight C, Sarda SP, Patel N, Wiseman C, de Castro NP, Nazir J, Kelly RJ. The cost-effectiveness, of pegcetacoplan compared with ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria, in a UK setting. J Comp Eff Res 2022; 11:969-985. [PMID: 35796199 DOI: 10.2217/cer-2022-0076] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by hemolytic anemia, bone marrow failure and thrombosis. We evaluated, the cost-effectiveness of pegcetacoplan, a novel proximal C3 inhibitor, versus ravulizumab in patients with PNH and hemoglobin levels <10.5 g/dl despite eculizumab treatment in the UK healthcare and social services setting. Materials & methods: A Markov cohort framework model, based on the data from the pivotal trial of pegcetacoplan (PEGASUS/NCT03500549), evaluated lifetime costs and outcomes. Patients transitioned through 3 PNH hemoglobin level/red blood cell transfusion health states. Results: Pegcetacoplan provides lower lifetime costs/greater quality-adjusted life years (£6,409,166/14.694QALYs, respectively) versus ravulizumab (£6,660,676/12.942QALYs). Conclusion: Pegcetacoplan is associated with enhanced anemia control, greater QALYs and reduced healthcare costs versus ravulizumab in the UK healthcare and social services setting.
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Affiliation(s)
- Zalmai Hakimi
- Swedish Orphan Biovitrum AB, Stockholm, SE-112 76, Sweden
| | - Koo Wilson
- Swedish Orphan Biovitrum AB, Stockholm, SE-112 76, Sweden
| | | | | | | | | | | | | | | | | | | | - Jameel Nazir
- Swedish Orphan Biovitrum AB, Stockholm, SE-112 76, Sweden
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Kulasekararaj AG, Brodsky RA, Nishimura JI, Patriquin CJ, Schrezenmeier H. The importance of terminal complement inhibition in paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol 2022; 13:20406207221091046. [PMID: 35663504 PMCID: PMC9160915 DOI: 10.1177/20406207221091046] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 03/14/2022] [Indexed: 11/30/2022] Open
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic hematologic disorder associated with inappropriate terminal complement activity on blood cells that can result in intravascular hemolysis (IVH), thromboembolic events (TEs), and organ damage. Untreated individuals with PNH have an increased risk of morbidity and mortality. Patients with PNH experiencing IVH often present with an elevated lactate dehydrogenase (LDH; ⩾ 1.5 × the upper limit of normal) level which is associated with a significantly higher risk of TEs, one of the leading causes of death in PNH. LDH is therefore used as a biomarker for IVH in PNH. The main objective of PNH treatment should therefore be prevention of morbidity and mortality due to terminal complement activation, with the aim of improving patient outcomes. Approval of the first terminal complement inhibitor, eculizumab, greatly changed the treatment landscape of PNH by giving patients an effective therapy and demonstrated the critical role of terminal complement and the possibility of modulating it therapeutically. The current mainstays of treatment for PNH are the terminal complement component 5 (C5) inhibitors, eculizumab and ravulizumab, which have shown efficacy in controlling terminal complement-mediated IVH, reducing TEs and organ damage, and improving health-related quality of life in patients with PNH since their approval by the United States Food and Drug Administration in 2007 and 2018, respectively. Moreover, the use of eculizumab has been shown to reduce mortality due to PNH. More recently, interest has arisen in developing additional complement inhibitors with different modes of administration and therapeutics targeting other components of the complement cascade. This review focuses on the pathophysiology of clinical complications in PNH and explores why sustained inhibition of terminal complement activity through the use of complement inhibitors is essential for the management of patients with this chronic and debilitating disease.
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Affiliation(s)
- Austin G. Kulasekararaj
- Department of Haematological Medicine, King’s College Hospital, Denmark Hill, London SE5 9RS, UK
- National Institute of Health Research/Wellcome King’s Clinical Research Facility and King’s College London, London, UK
| | | | - Jun-ichi Nishimura
- Department of Hematology and Oncology, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Christopher J. Patriquin
- Division of Medical Oncology & Hematology, University Health Network – Toronto General Hospital, University of Toronto, Toronto, ON, Canada
| | - Hubert Schrezenmeier
- Institute of Transfusion Medicine, University of Ulm, and Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Transfusion Service, and University Hospital Ulm, Ulm, Germany
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Garg A, Khanikar D, Shah S, Patel K, Shah K, Raj A, Panchal H, Patel A, Parikh S. Hematopoietic stem cell transplantation in paroxysmal nocturnal hemoglobinuria: Experience from a tertiary care center. JOURNAL OF APPLIED HEMATOLOGY 2022. [DOI: 10.4103/joah.joah_15_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Lu Y, Zhao YL, Xiong M, Sun RJ, Cao XY, Wei ZJ, Lu DP. Unmanipulated haploidentical donor and matched unrelated donor hematopoietic stem cell transplantation in patients with paroxysmal nocturnal hemoglobinuria: a single-center study. Leuk Lymphoma 2021; 63:1211-1219. [PMID: 34913818 DOI: 10.1080/10428194.2021.2015588] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
We analyzed the outcomes of 32 patients with paroxysmal nocturnal hemoglobinuria (PNH) who underwent either a haploidentical donor (HID) or a matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT). Seventeen patients received an HSCT from an HID and 15 patients received an HSCT from an MUD. The median follow-up time of the surviving patients was 36 months (range: 12-96 months). No significant differences were observed in the 3-year overall survival (OS) between the HID and MUD cohorts (74.1%±11.4% vs. 93.3%±6.4%, respectively, p=.222) or in the 3-year failure-free survival (68.8%±11.8% vs. 86.7%±8.8%, respectively, p=.307). Treatment-related mortality occurred in five patients. A univariate analysis of risk factors revealed platelet engraftment failure negatively impacted OS and FFS. We conclude that HID and MUD-HSCT are feasible and can be effective options for those PNH patients with concomitant bone marrow failure, recurrent life-threatening thrombosis, and uncontrollable hemolysis.
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Affiliation(s)
- Yue Lu
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Yan-Li Zhao
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Min Xiong
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Rui-Juan Sun
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Xing-Yu Cao
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Zhi-Jie Wei
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
| | - Dao-Pei Lu
- Department of Bone Marrow Transplantation, Hebei Yanda Lu Daopei Hospital, Langfang, China
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Yılmaz F, Soyer N, Cengiz Seval G, Civriz Bozdağ S, Topcuoğlu P, Ünal A, Kaynar L, Özgür G, Sucak G, Göker H, Velet M, Özdoğu H, Yılmaz M, Kaya E, Salim O, Deveci B, Karadoğan İ, Saydam G, Şahin F, Vural F. Hematopoietic Stem Cell Transplantation for Patients with Paroxysmal Nocturnal Hemoglobinuria with or without Aplastic Anemia: A Multicenter Turkish Experience. Turk J Haematol 2021; 38:195-203. [PMID: 34057336 PMCID: PMC8386301 DOI: 10.4274/tjh.galenos.2021.2021.0105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Objective: Although inhibition of the complement system at different steps is a promising therapy modality in patients with paroxysmal nocturnal hemoglobinuria (PNH), allogeneic hematopoietic stem cell transplantation (HCT) is still the only curative therapy, especially for patients with intractable hemolysis or bone marrow failure. The aim of this study is to evaluate the outcomes of allogeneic HCT in PNH patients with aplastic anemia (PNH-AA) or without. Materials and Methods: Thirty-five PNH/PNH-AA patients who were treated with allogeneic HCT in 10 transplantation centers in Turkey were retrospectively analyzed. Results: Sixteen (45.7%) and 19 (54.3%) patients were diagnosed with classical PNH and PNH-AA, respectively. The median age of the patients was 32 (18-51) years. The 2-year overall survival (OS) rate and rate of graft-versus-host disease-free, failure-free survival (GFFS) was 81.2% and 78.1%, respectively. The 2-year OS in cases of classical PNH and PNH-AA was 81.3% and 79.9%, respectively (p=0.87), and 2-year GFFS in cases of PNH and PNH-AA was 79% and 76% (p=0.977), without statistical significance. The OS and GFFS rates also did not differ between transplantations with matched sibling donors (MSDs) and matched unrelated donors (MUDs). Conclusion: Allogeneic HCT with MSDs or MUDs is a good option for selected patients with classical PNH and PNH-AA. In particular, patients with debilitating and refractory hemolysis and patients with bone marrow failure might form an excellent group of candidates for allogeneic HCT.
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Affiliation(s)
- Fergün Yılmaz
- Marmara University Faculty of Medicine, Department of Hematology, İstanbul, Turkey
| | - Nur Soyer
- Ege University Faculty of Medicine, Department of Hematology, İzmir, Turkey
| | | | - Sinem Civriz Bozdağ
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Pervin Topcuoğlu
- Ankara University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Ali Ünal
- Erciyes University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Leylagül Kaynar
- Erciyes University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Gökhan Özgür
- Medical Park Bahçeşehir Hospital, Clinic of Hematology and Transplantation, İstanbul, Turkey
| | - Gülsan Sucak
- Medical Park Bahçeşehir Hospital, Clinic of Hematology and Transplantation, İstanbul, Turkey
| | - Hakan Göker
- Hacettepe University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Mustafa Velet
- Hacettepe University Faculty of Medicine, Department of Hematology, Ankara, Turkey
| | - Hakan Özdoğu
- Başkent University Faculty of Medicine, Adana Bone Marrow Transplantation Center, Department of Hematology, Adana, Turkey
| | - Mehmet Yılmaz
- SANKO University Faculty of Medicine, Department of Hematology, Gaziantep, Turkey
| | - Emin Kaya
- İnönü University Faculty of Medicine, Department of Hematology, Malatya, Turkey
| | - Ozan Salim
- Akdeniz University Faculty of Medicine, Department of Hematology, Antalya, Turkey
| | - Burak Deveci
- İstanbul Gelişim University, Medstar Antalya Hospital Bone Marrow Transplantation Center, Department of Hematology, Antalya, Turkey
| | - İhsan Karadoğan
- İstanbul Gelişim University, Medstar Antalya Hospital Bone Marrow Transplantation Center, Department of Hematology, Antalya, Turkey
| | - Güray Saydam
- Ege University Faculty of Medicine, Department of Hematology, İzmir, Turkey
| | - Fahri Şahin
- Ege University Faculty of Medicine, Department of Hematology, İzmir, Turkey
| | - Filiz Vural
- Ege University Faculty of Medicine, Department of Hematology, İzmir, Turkey
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Du Y, Han B. Advances in Hematopoietic Stem Cell Transplantation for Patients with Paroxysmal Nocturnal Hemoglobinuria. Transplant Cell Ther 2020; 27:301-307. [PMID: 33840442 DOI: 10.1016/j.jtct.2020.11.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 11/05/2020] [Accepted: 11/05/2020] [Indexed: 01/29/2023]
Abstract
In the era of eculizumab, the number of patients with paroxysmal nocturnal hemoglobinuria (PNH) who undergo hematopoietic stem cell transplantation (HSCT) has decreased significantly. However, owing to the possibility of severe aplastic anemia (AA) or a suboptimal response to eculizumab, HSCT still plays an important role in the treatment of patients with PNH combined with AA or recurrent hemolysis-related symptoms despite its high level of risk. Here we review studies involving patients with PNH who underwent HSCT over the past 15 years and conclude that patients with refractory AA/PNH and patients with severe classical PNH are candidates for HSCT in countries where eculizumab is unavailable. The major causes of death from transplantation include graft-versus-host disease (GVHD), infection, and thrombotic microangiopathy. A haploidentical donor is a potential choice for patients without an HLA-matched donor. In addition, the use of eculizumab in combination with HSCT may help prevent GVHD.
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Affiliation(s)
- Yali Du
- Department of Hematology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences
| | - Bing Han
- Department of Hematology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences.
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Bektas M, Copley-Merriman C, Khan S, Sarda SP, Shammo JM. Paroxysmal nocturnal hemoglobinuria: current treatments and unmet needs. J Manag Care Spec Pharm 2020; 26:S14-S20. [PMID: 33356783 PMCID: PMC10410676 DOI: 10.18553/jmcp.2020.26.12-b.s14] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The current standard of care for paroxysmal nocturnal hemoglobinuria (PNH) are the C5 inhibitors eculizumab and ravulizumab, both monoclonal antibodies designed to target the complement protein C5, thereby preventing its cleavage and the formation of the terminal attack complex. C5 inhibitors have yielded substantial improvements in the treatment of PNH and changed the mortality and morbidity, as well as health-related quality of life of patients with the disease. These treatments target underlying intravascular hemolysis; however, they do not address extravascular hemolysis, resulting in incomplete response and remaining symptoms in some patients. Therefore, despite treatment with a C5 inhibitor, some patients still experience anemia with associated fatigue, transfusion needs, and impaired health-related quality of life. DISCLOSURES: This research was developed under a research contract between RTI Health Solutions and Apellis Pharmaceuticals and was funded by Apellis Pharmaceuticals. Bektas, Copley-Merriman, and Khan are employees of RTI Health Solutions. Sarda is an employee of Apellis Pharmaceuticals. Shammo consults for Apellis Pharmaceuticals.
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Affiliation(s)
- Meryem Bektas
- Market Access and Outcomes Strategy, RTI Health Solutions, Research Triangle, NC
| | | | - Shahnaz Khan
- Market Access and Outcomes Strategy, RTI Health Solutions, Research Triangle, NC
| | - Sujata P Sarda
- Global Health Economics and Outcomes Research, Apellis Pharmaceuticals, Waltham, MA
| | - Jamile M Shammo
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL
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12
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Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with paroxysmal nocturnal hemoglobinuria. Int J Hematol 2020; 113:122-127. [PMID: 32889696 DOI: 10.1007/s12185-020-02982-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2020] [Revised: 07/25/2020] [Accepted: 08/25/2020] [Indexed: 10/23/2022]
Abstract
The safety and efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for paroxysmal nocturnal hemoglobinuria (PNH) remain unclear. Therefore, we retrospectively analyzed the outcomes of 42 adult patients with PNH who underwent allogeneic HSCT using the registry database of the Japan Society for Hematopoietic Cell Transplantation. The median patient age was 32.5 years. The number of packed red cell (PRC) transfusions was < 20 times in 19 patients and ≥ 20 times in 16; 7 patients had missing data. Stem cell sources were bone marrow (N = 15) or peripheral blood (N = 13) from a related donor or bone marrow (N = 11) and cord blood (N = 3) from an unrelated donor. The cumulative incidence of neutrophil engraftment at day 40 was 81%. Six patients died before engraftment, and the 6-year overall survival (OS) was 74%. The OS of patients with < 20 pretransplant PRC transfusions was significantly higher than that of patients with ≥ 20 pretransplant PRC transfusions (95% vs. 63%; P < 0.05). Moreover, the OS of patients aged < 30 years was significantly higher than that of patients aged ≥ 30 years (90% vs. 59%; P < 0.05). Allogeneic HSCT for PNH could provide favorable survival; however, pretransplant transfusion burden and patient age should be considered when deciding the timing of allogeneic HSCT.
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13
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Allogeneic Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria: Multicenter Analysis by the Polish Adult Leukemia Group. Biol Blood Marrow Transplant 2020; 26:1833-1839. [PMID: 32512214 DOI: 10.1016/j.bbmt.2020.05.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/28/2020] [Accepted: 05/28/2020] [Indexed: 11/23/2022]
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the sole potential cure for paroxysmal nocturnal hemoglobinuria (PNH); however, the data on its utility in PNH are limited. This retrospective analysis of patients with PNH who underwent allo-HSCT in 11 Polish centers between 2002 and 2016 comprised 78 patients with PHN, including 27 with classic PNH (cPNH) and 51 with bone marrow failure-associated PNH (BMF/PNH). The cohort was 59% male, with a median age of 29 years (range, 12 to 65 years). There was a history of thrombosis in 12% and a history of hemolysis in 81%, and 92% required erythrocyte transfusions before undergoing allo-HSCT. No patient received eculizumab, and 26% received immunosuppressive treatment. The median time from diagnosis to allo-HSCT was 12 months (range, 1 to 127 months). Almost all patients (94%) received reduced-toxicity conditioning, 66% with treosulfan. The stem cell source was peripheral blood in 72% and an identical sibling donor in 24%. Engraftment occurred in 96% of the patients. With a median follow-up of 5.1 years in patients with cPNH and 3.2 years in patients with BMF/PNH, 3-year overall survival (OS) was 88.9% in the former and 85.1% in the latter (P = not significant [NS]). The 3-year OS for patients with/without thrombosis was 50%/92% (P = NS) in the cPNH group and 83.3%/85.3% (P = NS) in the BMF/PNH group. The 3-year OS for in the BMF/PNH patients with/without hemolysis was 93.9%/62.9% (hazard ratio, .13; P = .016). No other factors impacted OS. After allo-HSCT, the frequency of the PNH clone was reduced to 0%, <1%, and <2.4% in 48%, 48%, and 4% of cPNH patients and in 84%, 11%, and 5% of BMF/PNH patients, respectively. The frequency of acute graft-versus-host disease (GVHD) grade II-IV was 23%, and the cumulative 1-year incidence of extensive chronic GVHD was 10.8% in the BMF/PNH group and 3.7% in the cPNH group. Allo-HSCT is a valid option for PNH patients, effectively eliminating the PNH clone with satisfactory overall survival and acceptable toxicity. Reduced-toxicity conditioning with treosulfan is effective and safe in patients with cPNH and BMF/PNH.
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14
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Liu LM, Zhou HF, Wang QY, Qiu HY, Tang XW, Han Y, Fu CC, Jin ZM, Chen SN, Sun AN, Miao M, Wu DP. [Comparison of haploidentical hematopoietic stem cell transplantation and matched-sibling donor transplantation for the treatment of paroxysmal nocturnal hemoglobinuria]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2019; 40:306-311. [PMID: 31104442 PMCID: PMC7343014 DOI: 10.3760/cma.j.issn.0253-2727.2019.04.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/10/2018] [Indexed: 11/12/2022]
Abstract
Objective: To compare the outcomes between haploidentical donor hematopoietic stem cell transplantation (haplo-HSCT) and matched-sibling donor transplantation (MSD-HSCT) for paroxysmal nocturnal hemoglobinuria (PNH) . Methods: The clinical data of 40 PNH patients received HSCT (haplo-HSCT=25, MSD-HSCT=15) from July 2007 to May 2018 were analyzed retrospectively to compare the outcomes between haplo-HSCT and MSD-HSCT groups. Results: There were no differences in terms of gender, age, patients of PNH-AA and median time from diagnosis to transplantation between the 2 groups (P>0.05) . The median values of absolute mononuclear cell counts and CD34+ cells infused were 10.74 (4.80-22.86) ×108/kg and 12.19 (5.14-17.25) ×108/kg (P=0.866) , 3.57 (0.68-7.80) ×106/kg and 4.00 (3.02-8.42) ×106/kg (P=0.151) respectively, in haplo-HSCT and MSD-HSCT groups. All patients attained complete engraftment, no patient occurred graft failure. The median durations for myeloid and platelet engraftment were 12 (range, 9-26) and 11 (range, 7-15) days (P=0.065) , 19 (range, 11-75) and 13 (range, 11-25) days (P=0.027) respectively, in haplo-HSCT and MSD-HSCT groups. During a median follow-up of 26 (4-65) months in haplo-HSCT and 36 (4-132) months in MSD-HSCT groups (P=0.294) , the incidences of grade Ⅰ-Ⅳ acute graft-versus-host disease (aGVHD) were 32.0% and 20.0% (P=0.343) , grade Ⅱ-Ⅳ aGVHD were 16.0%, 13.3% (P=0.759) , chronic GVHD were 30.7% and 24.6% (P=0.418) , moderate-severe chronic GVHD were 12.7% and 7.1% (P=0.522) respectively, in haplo-HSCT and MSD-HSCT groups. The incidences of infection were 32.0% (8/25) and 26.7% (4/15) (P=1.000) respectively, in haplo-HSCT and MSD-HSCT groups. No patients occurred early death and relapse. Three-year estimated overall survival (OS) were (86.5±7.3) % and (93.3 ±6.4) % (P=0.520) , GVHD-free and failure-free survival (GFFS) were (78.3±8.6) % and (92.9±6.9) % (P=0.250) respectively, in haplo-HSCT and MSD-HSCT groups. Conclusion: The preliminary results indicated that haplo-HSCT was a feasible choice for PNH with favorable outcomes, haplo-HSCT and MSD-HSCT produced similar therapeutic efficacy.
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Affiliation(s)
- L M Liu
- The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, Suzhou 215006, China
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15
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Liu L, Liu S, Zhang Y, Zhou H, Wang Q, Tian H, Chen F, Qiu H, Tang X, Han Y, Fu C, Jin Z, Chen S, Sun A, Miao M, Wu D. Excellent Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Paroxysmal Nocturnal Hemoglobinuria: A Single-Center Study. Biol Blood Marrow Transplant 2019; 25:1544-1549. [PMID: 30853571 DOI: 10.1016/j.bbmt.2019.02.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Accepted: 02/28/2019] [Indexed: 10/27/2022]
Abstract
We analyzed the outcomes of 44 patients with paroxysmal nocturnal hemoglobinuria (PNH) who received allogeneic hematopoietic stem cell transplantation (allo-HSCT) (haploidentical [haplo]-donors, 25; matched sibling donors [MSDs], 15; and matched unrelated donors, 4) between July 2007 and May 2018. All patients achieved successful donor engraftment. The median time was 12 days (range, 7 to 26) for myeloid engraftment and 13 days (range, 11 to 75) for platelets. The cumulative incidences were 15.91% and 2.27% for grades II to IV and grades III to IV acute graft-versus-host disease (GVHD), respectively, with a median follow-up time of 36 months (range, 4 to 132). The cumulative incidences were 26.73% for chronic GVHD and 9.70% for moderate to severe chronic GVHD. No patients relapsed. The probabilities of 3-year overall survival (OS) and GVHD-free, failure-free survival (GFFS) were 90.4% ± 4.6% and 85.6% ± 5.4%, respectively. The 3-year OS rates of the haplo-donor and MSD groups were 86.5% ± 7.3% versus 93.3% ± 6.4% (P = .520). The 3-year GFFS rates of the haplo-donor and MSD groups were 78.3% ± 8.6% versus 92.9% ± 6.9% (P = .250). The preliminary results indicated that allo-HSCT is a feasible option for patients with PNH; however, this should not be considered as a first-choice therapy, because the results seemed to only suggest rather than confirm that haplo-HSCT and MSD-HSCT exerted similar therapeutic efficacies.
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Affiliation(s)
- Limin Liu
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Shan Liu
- Department of Laboratory Medicine, Affiliated Hospital of University of Electronic Science and Technology of China, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Yanming Zhang
- Department of Hematology, The Affiliated Huai'an Hospital of Xuzhou Medical University and The Second People's Hospital of Huai'an, Huai'an, China
| | - Huifen Zhou
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Qingyuan Wang
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Hong Tian
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Feng Chen
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Huiying Qiu
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Xiaowen Tang
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Yue Han
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Chengcheng Fu
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Zhengming Jin
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Suning Chen
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Aining Sun
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China
| | - Miao Miao
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China.
| | - Depei Wu
- Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Collaborative Innovation Center of Hematology, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou, China.
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Hematopoietic Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria in the Age of Eculizumab. Biol Blood Marrow Transplant 2019; 25:1331-1339. [PMID: 30711779 DOI: 10.1016/j.bbmt.2019.01.033] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 01/28/2019] [Indexed: 01/07/2023]
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic cell disease characterized by the destruction of hematopoietic cells through activation of the complement system with manifestations that can be life-threatening including hemolysis, thrombosis, and marrow failure. Allogeneic hematopoietic cell transplantation (HCT) remains the sole cure for PNH, but eculizumab, a terminal complement inhibitor of C5, has been used to prevent complement-mediated hemolysis in patients with PNH since its approval by the Food and Drug Administration in 2007. We examined outcomes of HCT in patients with PNH to evaluate the effects of disease subtype, conditioning intensity, and eculizumab use either pre-HCT or post-HCT. Fifty-five patients with a diagnosis of PNH underwent at least 1 HCT, with 4 patients requiring a second HCT for graft failure. The median age at the time of first HCT was 30.0 years (range, 4.2 to 66.9 years). Seventeen patients (30.9%) had classical PNH, and the remaining 38 patients had PNH associated with another marrow disorder (aplastic anemia in 26 of the 38). Indications for HCT included pancytopenia in 47.3% of the patients, myeloid malignancy (myelodysplastic syndrome, myeloproliferative neoplasm, or acute myelogenous leukemia) in 21.8%, recurrent hemolysis in 20.0%, and thrombosis in 10.9%. Of the 55 first HCTs, 26 were performed with myeloablative conditioning, 27 were performed with reduced-intensity conditioning, and 2 sets of identical twins underwent HCT without any conditioning. Donor types included HLA-matched related in 38.2%, HLA-matched unrelated in 34.5%, single HLA-allele mismatched unrelated in 16.4%, umbilical cord blood in 5.5%, syngeneic in 3.6%, and HLA-haploidentical in 1.8%. The median duration of follow-up in surviving patients was 6.1 years (range, 2.1 to 46.1 years) after first HCT. The median time to neutrophil and platelet engraftment was 17 days and 19 days, respectively; all but 2 patients (96.3%) had sustained engraftment. Overall survival was 70% at 5 years. Neither the choice of conditioning intensity nor PNH subtype affected survival. Nineteen patients died during follow-up, including 12 patients before day +365. Six patients received treatment with eculizumab before HCT, and 2 were treated after HCT. All patients treated with eculizumab were alive at a median follow-up of 2.3 years (range, .2 to 6.9 years). Both patients treated with eculizumab after HCT had minimal to no acute GVHD (aGVHD), with grade I skin aGVHD in 1 patient and no aGVHD in the other patient, and no chronic GVHD at 2.1 and 4.1 years post-HCT, respectively. With the approval of eculizumab, the indications for HCT include persistent hemolysis, persistent thrombosis, and associated marrow failure. Administration of eculizumab before and after HCT warrants further study, particularly considering our observation of minimal to no GVHD in 2 patients who received eculizumab after HCT.
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17
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Xia J, Chen SN, Chen J, Fan Y, Chen F, Ma X, Miao M, Wu DP. [Efficacy and safety of haploidentical hematopoietic stem cell transplantation for 17 patients with paroxysmal nocturnal hemamoglobinuria]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2018; 39:904-907. [PMID: 30486585 PMCID: PMC7342361 DOI: 10.3760/cma.j.issn.0253-2727.2018.11.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/22/2018] [Indexed: 01/07/2023]
Abstract
Objective: To explore the efficacy and safety of haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) for paroxysmal nocturnal hemoglobinuria (PNH). Methods: A total of 17 patients with PNH who received Haplo-HSCT from January 2013 to September 2017 were analyzed retrospectively. Results: Of them, 4 patients had de novo PNH, 13 patients had aplastic anemia-PNH syndrome (AA-PNH). All patients received modified busulfan and Cytoxan (BuCy)-based regimens combined with anti-thymocyte globulin (ATG). Granulocyte colony-stimulating factor-mobilized bone marrow and peripheral blood stem cells were transplanted as graft. Prophylaxis for graft-versus-host disease (GVHD) was ciclosporin A+ mycophenolate mofetil (MMF)+short-term methotrexate (MTX). All patients were engrafted successfully. The median time of neutrophils to 0.5×10(9)/L and platelets to 20×10(9)/L was 12(10-15) days and 14(11-45) days, respectively. All of the 17 patients achieved full donor chimerism at 30 d after Haplo-HSCT. Seven patients developed grade Ⅱ-Ⅳ acute GVHD, and 4 chronic GVHD. Median follow-up time was 27.1 (8.6-60.4) months. Of the 17 patients, 15 survived and 2 died of severe pulmonary infection and transplant associated thrombotic microangiopathy. Three-year overall survival was (77.8±15.2)%. Conclusion: Haplo-HSCT may be effective and safe for PNH patients who did not have matched donor.
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Affiliation(s)
- J Xia
- Jiangsu Institute of Hematology, Department of Hematology, the First Affiliated Hospital of Soochow University, Key Lab of Thrombosis and Hemostasis of Ministry of Health, Suzhou 215006, China
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18
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Patriquin CJ, Kiss T, Caplan S, Chin-Yee I, Grewal K, Grossman J, Larratt L, Marceau D, Nevill T, Sutherland DR, Wells RA, Leber B. How we treat paroxysmal nocturnal hemoglobinuria: A consensus statement of the Canadian PNH Network and review of the national registry. Eur J Haematol 2018; 102:36-52. [PMID: 30242915 DOI: 10.1111/ejh.13176] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/07/2018] [Indexed: 12/27/2022]
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease characterized by intravascular hemolysis, thrombophilia, and marrow failure. Its phenotype is due to absent or reduced expression of GPI-linked complement regulators and subsequent sensitivity of hematopoietic cells to complement-mediated damage and lysis. Introduction of the terminal complement inhibitor eculizumab drastically improved outcomes in PNH patients; however, despite this improvement, there remain several challenges faced by PNH patients and physicians who care for them. One of the most important is increasing awareness of the heterogeneity with which patients can present, which can lead to significant delays in recognition. Data from the Canadian PNH Registry are presented to demonstrate the variety of presenting symptoms. In Canada, geography precludes consolidation of care to just a few centers, so management is distributed across academic hospitals, linked together as the Canadian PNH Network. The Network over the last several years has developed educational programs and clinical checklists and has worked to standardize access to diagnostics across the country. Herein, we address some of the common diagnostic and therapeutic challenges faced by PNH physicians and give our recommendations. Gaps in knowledge are also addressed, and where appropriate, consensus opinion is provided.
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Affiliation(s)
| | - Thomas Kiss
- Division of Hematology, Oncology and Transplantation, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Québec, Canada
| | - Stephen Caplan
- Transfusion Services, Jewish General Hospital, Montreal, Quebec, Canada
| | - Ian Chin-Yee
- Divisions of Hematology and Pathology & Laboratory Medicine, Schulich School of Medicine, Western University, London, Ontario, Canada
| | - Kuljit Grewal
- Department of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Jennifer Grossman
- Division of Hematology and Hematological Malignancies, University of Calgary, Calgary, Alberta, Canada
| | - Loree Larratt
- Division of Hematology, University of Alberta, Edmonton, Alberta, Canada
| | - Daniele Marceau
- Division of Hematology and Oncology, Laval University, Quebec City, Quebec, Canada
| | - Tom Nevill
- Leukemia/BMT Program of British Columbia, BC Cancer Agency, Vancouver, British Columbia, Canada
| | | | - Richard A Wells
- Odette Cancer Centre, Sunnybrook Health Sciences, Toronto, Ontario, Canada
| | - Brian Leber
- Division of Hematology & Thromboembolism, McMaster University, Hamilton, Ontario, Canada
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19
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Fu HX, Huang XJ. [Advances in haploidentical hematopoietic stem cell transplantation for non-malignant hematological diseases]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2018; 39:691-696. [PMID: 30180476 PMCID: PMC7342844 DOI: 10.3760/cma.j.issn.0253-2727.2018.08.018] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/24/2018] [Indexed: 11/05/2022]
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20
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Mercuri A, Farruggia P, Timeus F, Lombardi L, Onofrillo D, Putti MC, Pillon M, Cantarini ME, Corti P, Tridello G, De Bortoli M, Pegoraro A, Cesaro S. A retrospective study of paroxysmal nocturnal hemoglobinuria in pediatric and adolescent patients. Blood Cells Mol Dis 2017; 64:45-50. [PMID: 28380398 DOI: 10.1016/j.bcmd.2017.03.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/13/2017] [Accepted: 03/17/2017] [Indexed: 11/20/2022]
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease, especially in children, characterized by intravascular hemolysis, thrombotic events, serious infections and bone marrow failure. We describe 16 patients who were diagnosed with PNH in childhood or adolescence. The time interval between the onset of symptoms and the PNH diagnosis and its treatment were compared in patients with classic PNH versus PNH associated with bone marrow disorder (PNH/BMD). A greater delay in diagnosis was observed in classic PNH compared to PNH/BMD patients. The first group of patients had higher levels of LDH, total bilirubin and absolute reticulocyte count and a bigger PNH clone size compared to PNH/BMD patients; also thrombotic events were observed only in the classic form of PNH. Conversely, PNH/BMD patients showed lower median levels of platelets. Apart from standard supportive measures, four patients with classic PNH received eculizumab whereas four patients with PNH/BMD underwent hematopoietic stem cell transplantation. Our series confirm that the most frequent presentation of PNH in the pediatric-adolescent age is PNH/BMD. The delay between the onset of symptoms and PNH diagnosis is relevant principally in the classic form. Moreover, our study showed that any case of unexpected thrombosis represents a criterium to perform a PNH screening.
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Affiliation(s)
- Angela Mercuri
- U.O.C Oncoematologia Pediatrica-AOUI Verona, P.le L.A. Scuro 10, 37134 Verona, Italy.
| | - Piero Farruggia
- Pediatric Hematology and Oncology Unit, Oncology Department, A.R.N.A.S. Ospedali Civico, Di Cristina e Benfratelli, Piazza Nicola Leotta 4, 90127 Palermo, Italy
| | - Fabio Timeus
- S.C. Oncoematologia Pediatrica e Centro Trapianti-Presidio Infantile Regina Margherita-A.O.U. Città della Salute e della Scienza, Piazza Polonia 94, 10126 Torino, Italy
| | - Laura Lombardi
- UOC Ematologia-Dipart. di Biotecnologie Cellulari ed Ematologia-Policlinico Umberto I Università " Sapienza"di Roma, via Benevento 6, 00161 Roma, Italy
| | - Daniela Onofrillo
- UOS di Oncoematologia Pediatrica, Dipartimento di Ematologia, Medicina Trasfusionale e Biotecnologie-Ospedale Spirito Santo, via Fonte Romana 8, 65123 Pescara, Italy
| | - Maria Caterina Putti
- Oncoematologia Pediatrica- Azienda Ospedaliera di Padova, Via N. Giustiniani 3, 35128 Padova, Italy.
| | - Marta Pillon
- Oncoematologia Pediatrica- Azienda Ospedaliera di Padova, Via N. Giustiniani 3, 35128 Padova, Italy
| | - Maria Elena Cantarini
- Oncologia ed Ematologia Pediatrica, U.O. Pediatria- Pession, Dipartimento per la salute della donna, del bambino e delle malattie urologiche, Azienda Ospedaliero-Universitaria Sant'Orsola-Malpighi, via Massarenti 11, 40138 Bologna, Italy
| | - Paola Corti
- Clinica Pediatrica-Università Milano Bicocca, Fondazione Monza e Brianza Bambino Mamma, via Pergolesi 33, 20900 Monza, Italy
| | - Gloria Tridello
- U.O.C Oncoematologia Pediatrica-AOUI Verona, P.le L.A. Scuro 10, 37134 Verona, Italy
| | | | - Anna Pegoraro
- U.O.C Oncoematologia Pediatrica-AOUI Verona, P.le L.A. Scuro 10, 37134 Verona, Italy
| | - Simone Cesaro
- U.O.C Oncoematologia Pediatrica-AOUI Verona, P.le L.A. Scuro 10, 37134 Verona, Italy
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21
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Kamranzadeh Fumani H, Zokaasadi M, Kasaeian A, Alimoghaddam K, Mousavi SA, Bahar B, Vaezi M, Ghavamzadeh A. Allogeneic hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: a retrospective single-center study. Hematol Oncol 2016; 35:935-938. [PMID: 27761934 DOI: 10.1002/hon.2367] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 08/31/2016] [Accepted: 09/19/2016] [Indexed: 11/11/2022]
Affiliation(s)
- Hosein Kamranzadeh Fumani
- Hematology, Oncology and Stem Cell Transplantation Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Mohammad Zokaasadi
- Hematology, Oncology and Stem Cell Transplantation Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Amir Kasaeian
- Hematology, Oncology and Stem Cell Transplantation Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Kamran Alimoghaddam
- Hematology, Oncology and Stem Cell Transplantation Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Seyed Asadollah Mousavi
- Hematology, Oncology and Stem Cell Transplantation Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Babak Bahar
- Hematology, Oncology and Stem Cell Transplantation Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Mohammad Vaezi
- Hematology, Oncology and Stem Cell Transplantation Research Center; Tehran University of Medical Sciences; Tehran Iran
| | - Ardeshir Ghavamzadeh
- Hematology, Oncology and Stem Cell Transplantation Research Center; Tehran University of Medical Sciences; Tehran Iran
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Sahin F, Akay OM, Ayer M, Dal MS, Ertop S, Ilhan O, Karakus V, Ozcan MA, Ozkocaman V, Ozsan H, Salim O, Tobu M, Tombak A, Tuglular TF, Yilmaz M, Unal A, Yenerel MN, Saydam G. Pesg PNH diagnosis, follow-up and treatment guidelines. AMERICAN JOURNAL OF BLOOD RESEARCH 2016; 6:19-27. [PMID: 27570707 PMCID: PMC4981648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/01/2016] [Accepted: 06/28/2016] [Indexed: 06/06/2023]
Abstract
PNH Education and Study Group (PESG) have been established in December 2013 as a non-profit, independent, medical organization www.pesg.org. Paroxysmal Nocturnal Hemoglobinuria (PNH) is a multi-systemic disease that should be treated with a multidisciplinary approach. Patients may apply to the clinics other than the hematology due to variability and diversity of clinical findings which lower the rate of diagnosis due to low awareness about PNH. PNH might be overlooked and diagnosis might be delayed. Regarding these, PESG was established with the collaboration of Immunology, Cardiology, Thorax Diseases (Pulmonology), Neurology, Gastroenterology, General Surgery and Urology specialists in addition to hematologists dealing with PNH. The PESG study group aims to increase the awareness about PNH, including training activities about PNH, strengthening the relations between clinics and planning of clinical studies as a goal. It is the first professional organization focusing on PNH, in Turkey.In this guideline, we want to facilitate the diagnosis attributes of physicians from all specializations that deal with PNH and its systemic complications. One can perceive this as a tailor made guideline of international guidelines but not a compilation.
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Affiliation(s)
- Fahri Sahin
- Department of Hematology, Ege UniversityIzmir, Turkey
| | | | - Mesut Ayer
- Department of Hematology, Haseki Training and Research HospitalIstanbul, Turkey
| | - Mehmet Sinan Dal
- Department of Hematology, Dr. Abdurrahman Yurtaslan Ankara Oncology Training and Research HospitalAnkara, Turkey
| | - Sehmus Ertop
- Department of Hematology, Bulent Ecevit UniversityZonguldak, Turkey
| | - Osman Ilhan
- Department of Hematology, Ankara UniversityAnkara, Turkey
| | - Volkan Karakus
- Department of Hematology, Mugla Sıtkı Kocman UniversityMugla, Turkey
| | | | | | - Hayri Ozsan
- Department of Hematology, Dokuz Eylul UniversityIzmir, Turkey
| | - Ozan Salim
- Department of Hematology, Akdeniz UniversityAntalya, Turkey
| | - Mahmut Tobu
- Department of Hematology, Ege UniversityIzmir, Turkey
| | - Anil Tombak
- Department of Hematology, Mersin UniversityMersin, Turkey
| | | | - Mehmet Yilmaz
- Department of Hematology, Gaziantep UniversityGaziantep, Turkey
| | - Ali Unal
- Department of Hematology, Erciyes UniversityKayseri, Turkey
| | | | - Guray Saydam
- Department of Hematology, Ege UniversityIzmir, Turkey
- On behalf of PNH Education and Study Group (PESG)
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Tian H, Liu L, Chen J, Xu Y, Jin Z, Miao M, Fu Z, Qiu H, Sun A, Wu D. Haploidentical hematopoietic stem cell transplant in paroxysmal nocturnal hemoglobinuria. Leuk Lymphoma 2016; 57:835-41. [DOI: 10.3109/10428194.2015.1068309] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Sun XS, Liu X, Xu KL, Chen A, Rybka WB, Pu JJ. Advances and perspectives on cellular therapy in acquired bone marrow failure diseases. World J Hematol 2016; 5:31-36. [DOI: 10.5315/wjh.v5.i1.31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2015] [Revised: 10/24/2015] [Accepted: 01/07/2016] [Indexed: 02/05/2023] Open
Abstract
Acquired bone marrow failure diseases (ABMFD) are a class of hematopoietic stem cell diseases with a commonality of non-inherited disruption of hematopoiesis that results in pancytopenia. ABMFDs also are a group of heterogeneous diseases with different etiologies and treatment options. The three most common ABMFDs are aplastic anemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria. Stem cell transplantation is the only treatment that can cure these diseases. However, due to high therapy-related mortality, stem cell transplantation has rarely been used as a first line treatment in treating ABMFD. With the advance of personalized medicine and precision medicine, various novel cellular therapy strategies are in trial to increase the efficiency and efficacy of ABMFD treatment. This article aims to review current available stem cell transplantation protocols and promising cellular therapy research in treating ABMFD.
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Chen F, Wu D, Tang X, Miao M, Fu C, Qiu H, Jin Z, Xue S, Ma X, Sun A, Chang W, Ruan C. [Outcomes of allogeneic hematopoietic stem cell transplantation for 18 patients with paroxysmal nocturnal haemoglobinuria]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2015; 36:1005-10. [PMID: 26759101 PMCID: PMC7342317 DOI: 10.3760/cma.j.issn.0253-2727.2015.12.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To evaluate the outcomes of allogeneic hematopoietic stem cell transplantation（allo-HSCT）for paroxysmal nocturnal haemoglobinuria（PNH）and aplastic anemia（AA）- PNH syndrome. METHODS The clinical data of 18 PNH or AA-PNH patients, including 4 classic PNH and 14 AA-PNH, received allo-HSCT from Dec 2007 to Feb 2015 were analyzed retrospectively. Nine patients received HLA-haploidentical donor HSCT（1 patient received salvage HLA-haploidentical donor HSCT after the graft failure of double cord blood transplantation）, 7 patients received HLA-identical sibling donor HSCT, and 2 HLA-identical unrelated donor HSCT. The conditioning regimens were as follow: 13 patients received modified BU/CY- based regimens, 5 non- myeloablative regimens ［fludarabine （Flu） + antithymocyte globulin（ATG）+ cyclophosphamide（CY）or busulfan（BU）］. Prophylaxis for graft- versushost disease（GVHD）: the patients with HLA-identical sibling donor received cyclosporine（CsA）plus short-term methotrexate（MTX）, the patients with HLA -haploidentical donor or HLA-identical unrelated donor received CsA or tacrolimus（FK506）+ mycophenolate mofetil（MMF）+ short- term methotrexate （MTX）. RESULTS All patients were engrafted successfully（1 patient engrafted by haploidentical donor after the graft failure of double cord blood transplantation）. The median days of neutrophils（ANC）above 0.5 × 109/L and platelets （PLT） more than 20 × 10⁹/L were 11（10- 26）days and 15（11- 120）days, respectively. Three patients（17.6%）developed acute GVHD（aGVHD）, 2 for grade Ⅱ aGVHD, 1 for grade Ⅳ aGVHD. Of 16 patients, 2 occurred limited chronic GVHD（cGVHD）. After a median follow-up of 14.6（2.0-86.7）months, 3 patients（17.6%）died, out of which one died of severe aGVHD, one died of severe pulmonary infection, one pulmonary infection with transplant- associated thrombotic microangiopathy. The 5- year estimated disease free survival was（80.5 ± 10.2）%. No patient relapsed. CONCLUSION Allo-HSCT is an effective and curable therapy for PNH or AA-PNH with improved prognosis, and offers a valid therapeutic option for these patients before humanized monoclonal antibody against C5 are widely used clinically.
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Affiliation(s)
- Feng Chen
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Depei Wu
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Xiaowen Tang
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Miao Miao
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Chengcheng Fu
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Huiying Qiu
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Zhengming Jin
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Shengli Xue
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Xiao Ma
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Aining Sun
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Weirong Chang
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Changgeng Ruan
- Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
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26
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Sahin F, Ozkan MC, Mete NG, Yilmaz M, Oruc N, Gurgun A, Kayikcioglu M, Guler A, Gokcay F, Bilgir F, Ceylan C, Bilgir O, Sari IH, Saydam G. Multidisciplinary clinical management of paroxysmal nocturnal hemoglobinuria. AMERICAN JOURNAL OF BLOOD RESEARCH 2015; 5:1-9. [PMID: 26171279 PMCID: PMC4497492] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 01/19/2015] [Indexed: 06/04/2023]
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease caused by clonal expansion of one or more hematopoietic stem cell (HSC) lines due to a somatic mutation of the phosphatidylinositol glycan anchor (PIG-A) gene located on Xp22.1. PNH incidence is 1.5-2 cases per million of the population per year. PNH can affect multiple systems in the body and requires multidisciplinary clinical management. Patients can manifest with severe pancytopenia, life-threatening thrombosis affecting the hepatic, abdominal, cerebral, and subdermal veins, and high requirements for blood transfusion due to haemolytic anemia. PNH can also be associated with bone marrow failure. Advances in diagnostic techniques and a targeted therapeutic approach for PNH have emerged in the last two decades. Eculizumab, a promising humanized monoclonal antibody against C5, is the first approved therapy for PNH.
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Affiliation(s)
- Fahri Sahin
- Department of Hematology, Ege UniversityIzmir
| | | | | | | | - Nevin Oruc
- Department of Gastroenterology, Ege UniversityIzmir
| | - Alev Gurgun
- Department of Pulmonary Medicine, Ege UniversityIzmir
| | | | - Ayse Guler
- Department of Neurology, Ege UniversityIzmir
| | | | - Ferda Bilgir
- Division of Immunology, Ataturk Education and Research Hospital, Katip Celebi UniversityIzmir
| | - Cengiz Ceylan
- Department of Hematology, Izmir Tepecik Education and Research HospitalIzmir
| | - Oktay Bilgir
- Department of Hematology, Izmir Bozyaka Training and Research HospitalIzmir
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27
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Zhu X, Zheng C, Tang B, Zhang L, Qiang P, Wan X, Zhang X, Liu H, Sun Z. [Unrelated cord blood transplantation in the treatment of paroxysmal nocturnal hemoglobinuria: a case report and literature review]. ZHONGHUA XUE YE XUE ZA ZHI = ZHONGHUA XUEYEXUE ZAZHI 2015; 36:532-3. [PMID: 26134024 PMCID: PMC7343071 DOI: 10.3760/cma.j.issn.0253-2727.2015.06.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Indexed: 11/16/2022]
Affiliation(s)
- Xiaoyu Zhu
- Department of Hematology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China
| | - Changcheng Zheng
- Department of Hematology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China
| | - Baolin Tang
- Department of Hematology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China
| | - Lei Zhang
- Department of Hematology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China
| | - Ping Qiang
- Department of Hematology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China
| | - Xiang Wan
- Department of Hematology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China
| | - Xuhan Zhang
- Department of Hematology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China
| | - Huilan Liu
- Department of Hematology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China
| | - Zimin Sun
- Department of Hematology, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei 230001, China
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28
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Marotta S, Pagliuca S, Risitano AM. Hematopoietic stem cell transplantation for aplastic anemia and paroxysmal nocturnal hemoglobinuria: current evidence and recommendations. Expert Rev Hematol 2014; 7:775-89. [DOI: 10.1586/17474086.2014.967678] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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29
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Schcolnik-Cabrera A, Labastida-Mercado N, Galindo-Becerra LS, Gomez-Almaguer D, Herrera-Rojas MA, Ruiz-Delgado GJ, Ruiz-Arguelles GJ. Reduced-intensity stem cell allografting for PNH patients in the eculizumab era: The Mexican experience. ACTA ACUST UNITED AC 2014; 20:263-6. [PMID: 25148373 DOI: 10.1179/1607845414y.0000000195] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Background Paroxysmal nocturnal haemoglobinuria (PNH) presents as two major entities: the classical form, predominantly haemolytic and a secondary type with marrow failure and resultant aplastic anaemia (AA-PNH). Currently, the treatment of choice of the haemolytic variant is eculizumab; however, the most frequent form of PNH in México is AA-PNH. Patients and methods Six consecutive AA-PNH patients with HLA-identical siblings were allografted in two institutions in México, employing a reduced-intensity conditioning regimen for stem cell transplantation (RIST) conducted on an outpatient basis. Results Median age of the patients was 37 years (range 25-48). The patients were given a median of 5.4 × 10(6)/kg allogeneic CD34(+) cells, using 1-3 apheresis procedures. Median time to achieve above 0.5 × 10(9)/l granulocytes was 21 days, whereas median time to achieve above 20 × 10(9)/l platelets was 17 days. Five patients are alive for 330-3150 days (median 1437) after the allograft. The 3150-day overall survival is 83.3%, whereas median survival has not been reached, being above 3150 days. Conclusion We have shown that hypoplastic PNH patients can be allografted safely using RIST and that the long-term results are adequate, the cost-benefit ratio of this treatment being reasonable. Additional studies are needed to confirm the usefulness of RIST in the treatment of AA-PNH.
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30
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Memon AR, Khan R, Rauf MUA, Shafique K. Paroxysmal nocturnal hemoglobinuria presenting as cerebral venous sinus thrombosis: a case report. Int Arch Med 2014; 7:39. [PMID: 25143784 PMCID: PMC4138960 DOI: 10.1186/1755-7682-7-39] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2014] [Accepted: 08/08/2014] [Indexed: 11/17/2022] Open
Abstract
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare type of acquired hemolytic anemia that is frequently associated with thrombophilia. It may rarely present with cerebral venous sinus thrombosis, which manifests clinically with signs of raised intracranial pressure and requires lifelong anticoagulation therapy. One such rare presentation was seen in a 28 years old male who had history of recurrent episodes of passing red colored urine and this time presented with severe headache. He was diagnosed to have cerebral venous sinus thrombosis and on further workup was found to be suffering from PNH.
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Affiliation(s)
- Abdul Rauf Memon
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | - Rizwan Khan
- Department of Medicine, Dow University of Health Sciences, Karachi, Pakistan
| | | | - Kashif Shafique
- School of Public Health, Dow University of Health Sciences, Karachi, Pakistan ; Institute of Health and Wellbeing, Public Health, University of Glasgow, 1-Lilybank Gardens, Glasgow G12 8RZ, UK
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31
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Pantin J, Tian X, Geller N, Ramos C, Cook L, Cho E, Scheinberg P, Vasu S, Khuu H, Stroncek D, Barrett J, Young NS, Donohue T, Childs RW. Long-term outcome of fludarabine-based reduced-intensity allogeneic hematopoietic cell transplantation for debilitating paroxysmal nocturnal hemoglobinuria. Biol Blood Marrow Transplant 2014; 20:1435-9. [PMID: 24844857 DOI: 10.1016/j.bbmt.2014.05.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2014] [Accepted: 05/13/2014] [Indexed: 11/29/2022]
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis, venous thrombosis, and bone marrow failure. Seventeen patients with debilitating PNH, including 8 who were HLA-alloimmunized, underwent a reduced-intensity allogeneic hematopoietic cell transplantation (HCT). All received cyclophosphamide/fludarabine +/- antithymocyte globulin followed by a granulocyte colony-stimulating factor-mobilized HCT from an HLA-matched relative. Glycosylphosphatidylinositol-negative neutrophils were detectable after engraftment but disappeared completely at a median 100 days after transplantation. With a median follow-up of nearly 6 years, 15 patients (87.8%) survived, all without any evidence of PNH, transfusion independent, and off anticoagulation. Allogeneic reduced-intensity HCT remains a curative therapeutic option for PNH patients who are not candidates for eculizumab treatment.
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Affiliation(s)
- Jeremy Pantin
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; Division of Hematology and Oncology, Department of Medicine, Georgia Regents University, Augusta, Georgia
| | - Xin Tian
- Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Nancy Geller
- Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Catalina Ramos
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Lisa Cook
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Elena Cho
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Phillip Scheinberg
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; Hospital São José - Hospital Beneficência Portuguesa de São Paulo, São Paulo, Brazil
| | - Sumithira Vasu
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; Division of Hematology, Department of Medicine, Wexner Medical Center, Ohio State University, Columbus, Ohio
| | - Hahn Khuu
- Department of Transfusion Medicine, Clinical Research Center, National Institutes of Health, Bethesda, Maryland
| | - David Stroncek
- Department of Transfusion Medicine, Clinical Research Center, National Institutes of Health, Bethesda, Maryland
| | - John Barrett
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Neal S Young
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Theresa Donohue
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland
| | - Richard W Childs
- Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland.
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Schrezenmeier H, Muus P, Socié G, Szer J, Urbano-Ispizua A, Maciejewski JP, Brodsky RA, Bessler M, Kanakura Y, Rosse W, Khursigara G, Bedrosian C, Hillmen P. Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. Haematologica 2014; 99:922-9. [PMID: 24488565 PMCID: PMC4008114 DOI: 10.3324/haematol.2013.093161] [Citation(s) in RCA: 172] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Accepted: 01/29/2014] [Indexed: 11/12/2022] Open
Abstract
Paroxysmal nocturnal hemoglobinuria is a rare, acquired disease associated with hemolytic anemia, bone marrow failure, thrombosis, and, frequently, poor quality of life. The International PNH Registry is a worldwide, observational, non-interventional study collecting safety, effectiveness, and quality-of-life data from patients with a confirmed paroxysmal nocturnal hemoglobinuria diagnosis or detectable paroxysmal nocturnal hemoglobinuria clone, irrespective of treatment. In addition to evaluating the long-term safety and effectiveness of eculizumab in a global population, the registry aims to improve diagnosis, optimize patient management and outcomes, and enhance the understanding of the natural history of paroxysmal nocturnal hemoglobinuria. Here we report the characteristics of the first 1610 patients enrolled. Median disease duration was 4.6 years. Median granulocyte paroxysmal nocturnal hemoglobinuria clone size was 68.1% (range 0.01-100%). Overall, 16% of patients had a history of thrombotic events and 14% a history of impaired renal function. Therapies included anticoagulation (31%), immunosuppression (19%), and eculizumab (25%). Frequently reported symptoms included fatigue (80%), dyspnea (64%), hemoglobinuria (62%), abdominal pain (44%), and chest pain (33%). Patients suffered from poor quality of life; 23% of patients had been hospitalized due to paroxysmal nocturnal hemoglobinuria-related complications and 17% stated that paroxysmal nocturnal hemoglobinuria was the reason they were not working or were working less. This international registry will provide an ongoing, valuable resource to further the clinical understanding of paroxysmal nocturnal hemoglobinuria.
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33
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Weitz I, Meyers G, Lamy T, Cahn JY, Uranga MT, García Vela JA, Sanz MA, Severino B, Kelly RJ, Hillmen P, Hill A. Cross-sectional validation study of patient-reported outcomes in patients with paroxysmal nocturnal haemoglobinuria. Intern Med J 2013; 43:298-307. [PMID: 22909078 DOI: 10.1111/j.1445-5994.2012.02924.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 07/23/2012] [Indexed: 12/18/2022]
Abstract
BACKGROUND Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired, clonal haemopoietic stem cell disorder that causes chronic intravascular haemolysis, increases the risk of thrombosis and results in significant patient morbidity and mortality. The symptoms of PNH may have a major impact on patient quality of life. AIMS To assess patient fatigue and health-related quality of life in 29 patients with PNH using the Functional Assessment of Chronic Illness Therapy Fatigue subscale version 4 (FACIT-Fatigue) and the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire-C30, version 3 (EORTC QLQ-C30). METHODS Following completion of the questionnaires, patients were interviewed to assess the validity, clarity, relevance and comprehensiveness of the assessments. RESULTS Overall, patients considered both the FACIT-Fatigue and EORTC QLQ-C30 instruments to be relevant and adequate in assessing the level of PNH-associated fatigue and other quality-of-life measures. The FACIT-Fatigue questionnaire was considered to be clear and to comprehensively cover PNH-related fatigue. The EORTC QLQ-C30 instrument was considered to be easy to understand, but of an overall lower relevance, although some differences between countries were observed. Patients suggested additional questions that could be incorporated into future EORTC QLQ-C30 versions to make it more relevant to PNH. CONCLUSIONS This study confirms the validity of the FACIT-Fatigue and the EORTC QLQ-C30 questionnaires in this patient population and their routine use should be considered in the management of patients with PNH.
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Affiliation(s)
- I Weitz
- Keck-USC School of Medicine, Los Angeles, California, USA
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Varela JC, Brodsky RA. Paroxysmal nocturnal hemoglobinuria and the age of therapeutic complement inhibition. Expert Rev Clin Immunol 2013; 9:1113-24. [PMID: 24168416 DOI: 10.1586/1744666x.2013.842896] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease of hematopoietic stem cells due to a mutation in the PIG-A gene leading to a deficiency of GPI-anchored proteins. Lack of two specific GPI-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that result in both intravascular and extravascular hemolysis. Free hemoglobin leads to nitric oxide depletion that mediates the pathophysiology of some of the common clinical signs of PNH. Clinical symptoms of PNH include evidence of hemolytic anemia, bone marrow failure, smooth muscle dystonias and thromboses. Treatment options for patients with PNH include bone marrow transplantation, a therapy associated with high morbidity and mortality, or treatment with the complement inhibitor eculizumab. Eculizumab is a first-in-class anti-complement drug that in PNH has been shown to block complement-mediated hemolysis, reduce transfusion dependency, reduce thromboembolic complications and improve the quality of life (QoL) of patients.
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Affiliation(s)
- Juan Carlos Varela
- Department of Medicine, The Johns Hopkins School of Medicine, Division of Hematology, 720 Rutland Ave., Ross Research Building, Room 1025, Baltimore, MD, 21205, USA
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35
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Takayasu V, Kanegae MY, Rays J. Paroxysmal nocturnal hemoglobinuria: rare cause of acute renal failure. AUTOPSY AND CASE REPORTS 2012; 2:61-64. [PMID: 31528589 PMCID: PMC6735578 DOI: 10.4322/acr.2012.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 10/23/2012] [Indexed: 11/26/2022] Open
Abstract
Paroxysmal nocturnal hemoglobinuria is a rare acquired disease, characterized by hemolytic anemia, recurrent infections, cytopenias, and vascular thrombosis. It occurs by non-malignant clonal expansion of one or more hematopoietic stem cells that acquired somatic mutations in PIG-A gene linked to chromosome X. This mutation results in lower erythrocyte expression of CD55 and CD59 surface proteins and consequently increased susceptibility to the complement system. The renal involvement is generally benign, resulting in mild impairment in urinary concentration. Acute renal failure requiring hemodialytic support accompanying PNH is rarely observed. The authors report a case of a 37-year-old male who presented with bicytopenia (hemolytic anemia and thrombocytopenia) associated with acute renal failure requiring dialysis. Diagnosis was challenging because of the rarity and unfamiliarity with this entity, but was confirmed by flow cytometry. In the course of the disease, acute pyelonephritis with multiple renal abscesses was diagnosed requiring prolonged antibiotic therapy. Patient outcome was favorable after the control of hemolysis and the infection treatment.
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Affiliation(s)
- Vilma Takayasu
- Department of Internal Medicine - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil
| | - Márcia Yoshie Kanegae
- Department of Internal Medicine - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil
| | - Jairo Rays
- Department of Internal Medicine - Hospital Universitário - Universidade de São Paulo, São Paulo/SP - Brazil
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Gerds AT, Scott BL. Last marrow standing: bone marrow transplantation for acquired bone marrow failure conditions. Curr Hematol Malig Rep 2012; 7:292-9. [PMID: 23065408 DOI: 10.1007/s11899-012-0138-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome are a spectrum of acquired marrow failure, having a common pathologic thread of both immune dysregulation and the development of abnormal hematopoiesis. Allogeneic hematopoietic cell transplantation plays a critical role in the treatment of these disorders and, for many patients, is the only treatment modality with demonstrated curative potential. In recent years, there have been many breakthroughs in the understanding of the pathogenesis of these uncommon disorders. The subsequent advances in non-transplant therapies, along with concurrent improvement in outcomes after hematopoietic cell transplantation, necessitate continual appraisal of the indications, timing, and approaches to transplantation for acquired marrow failure syndromes. We review here contemporary and critical new findings driving current treatment decisions.
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Affiliation(s)
- Aaron T Gerds
- Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, 1100 Fairview Avenue N, D1-100, Seattle, WA, 98109-1024, USA.
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Peffault de Latour R, Schrezenmeier H, Bacigalupo A, Blaise D, de Souza CA, Vigouroux S, Willemze R, Terriou L, Tichelli A, Mohty M, de Guibert S, Marsh JC, Passweg J, Yves Mary J, Socié G. Allogeneic stem cell transplantation in paroxysmal nocturnal hemoglobinuria. Haematologica 2012; 97:1666-73. [PMID: 22689687 DOI: 10.3324/haematol.2012.062828] [Citation(s) in RCA: 87] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND In the era of eculizumab, identifying patients with paroxysmal nocturnal hemoglobinuria who may benefit from allogeneic stem cell transplantation is challenging. DESIGN AND METHODS We describe the characteristics and overall survival of 211 patients transplanted for paroxysmal nocturnal hemoglobinuria in 83 EBMT centers from 1978 to 2007. Next, we conducted a comparison with a cohort of 402 non-transplanted patients with paroxysmal nocturnal hemoglobinuria diagnosed between 1950 and 2005 in 92 French centers. We compared the occurrence of complications (i.e. thromboembolism and aplastic anemia) using either an individual or a stratum-matching procedure. RESULTS After a median follow-up of 5 years, the 5-year overall survival rate ± standard error (%) was 68 ± 3 in the transplanted group (54 ± 7 in the case of thromboembolism, 69 ± 5 in the case of aplastic anemia without thromboembolism and 86 ± 6 in the case of recurrent hemolytic anemia without thromboembolism or aplastic anemia). Only thromboembolism as the indication for transplantation was associated with worse outcome (P=0.03). We identified 24 pairs of transplanted and non-transplanted patients with thromboembolism for the matched comparison, with worse overall survival for the transplanted patients (hazard ratio=10.0; 95% confidence interval, 1.3-78.1; P=0.007). This was confirmed by the global matching procedure (P=0.03). As regards aplastic anemia without thromboembolism, 30 pairs were identified for the matched comparison. It was not observed that transplanted patients had a significantly worse overall survival (hazard ratio=4.0; 95% confidence interval, 0.9-18.9; P=0.06). A global matching procedure was not feasible. CONCLUSIONS Allogeneic stem cell transplantation is probably not a suitable treatment option for life-threatening thromboembolism in paroxysmal nocturnal hemoglobinuria.
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Taniguchi K, Okada M, Yoshihara S, Sawada A, Tokugawa T, Ishii S, Kaida K, Ikegame K, Minagawa K, Matsui T, Ogawa H. Strategy for bone marrow transplantation in eculizumab-treated paroxysmal nocturnal hemoglobinuria. Int J Hematol 2011; 94:403-407. [PMID: 21927799 DOI: 10.1007/s12185-011-0931-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2011] [Revised: 08/25/2011] [Accepted: 08/26/2011] [Indexed: 11/28/2022]
Abstract
Although the recent introduction of eculizumab has had a significant impact on the management of paroxysmal nocturnal hemoglobinuria (PNH), bone marrow transplantation (BMT) remains the only therapeutic option for patients who develop severe aplasia in the clinical course of PNH. However, information regarding BMT for eculizumab-treated PNH patients is scarce, and two major points-the optimal duration of eculizumab therapy, and the optimal BMT conditioning regimen-remain unclear. Here, we describe the clinical course of a PNH patient who was successfully treated with unrelated reduced-intensity BMT. Eculizumab was discontinued 2 weeks prior to the initiation of the conditioning regimen, which consisted of fludarabine 180 mg/m(2), cyclophosphamide 100 mg/kg, rabbit anti-thymocyte globulin 2 mg/kg, and TBI 3 Gy. Complete donor chimerism was rapidly achieved in association with a rapid decrease in the proportion of PNH erythrocytes. The patient became transfusion-free immediately after BMT, and had no recurrence of hemolysis. The present case suggests that discontinuation of eculizumab before BMT and the use of a highly lymphoablative conditioning regimen may act as a successful treatment strategy in BMT for PNH. Further studies are warranted to evaluate the efficacy and safety of this treatment strategy.
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Affiliation(s)
- Kyoko Taniguchi
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Masaya Okada
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Satoshi Yoshihara
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan.
| | - Akihiro Sawada
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Tazuko Tokugawa
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Shinichi Ishii
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Katsuji Kaida
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Kazuhiro Ikegame
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
| | - Kentaro Minagawa
- Division of Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Toshimitsu Matsui
- Division of Hematology, Department of Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroyasu Ogawa
- Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan
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Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease that presents with protean manifestations. Clinical and laboratory investigation over the past 25 years has uncovered most of the basic science underpinnings of PNH and has led to the development of a highly effective targeted therapy. PNH originates from a multipotent hematopoietic stem cell (HSC) that acquires a somatic mutation in a gene called phosphatidylinositol glycan anchor biosynthesis, class A (PIG-A). The PIG-A gene is required for the first step in glycosylphosphatidylinositol (GPI) anchor biosynthesis. Failure to synthesize GPI anchors leads to an absence of all proteins that utilize GPI to attach to the plasma membrane. Two GPI-anchor proteins, CD55 and CD59, are complement regulatory proteins; their absence on the surface of PNH cells leads to complement-mediated hemolysis. The release of free hemoglobin leads to scavenging of nitric oxide and contributes to many clinical manifestations, including esophageal spasm, fatigue, and possibly thrombosis. Aerolysin is a pore-forming toxin that binds GPI-anchored proteins and kills normal cells, but not PNH cells. A fluorescinated aerolysin variant (FLAER) binds GPI-anchor and serves as a novel reagent diagnosing PNH. Eculizumab, a humanized monoclonal antibody against C5, is the first effective drug therapy for PNH.
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Affiliation(s)
- Jeffrey J Pu
- Division of Hematology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
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Luzzatto L, Gianfaldoni G, Notaro R. Management of Paroxysmal Nocturnal Haemoglobinuria: a personal view. Br J Haematol 2011; 153:709-20. [DOI: 10.1111/j.1365-2141.2011.08690.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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