Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories

Latour, Régis Peffault de; Mary, Jean Yves; Salanoubat, Célia; Terriou, Louis; Étienne, Gabriel; Mohty, Mohamad; Roth, Sophie; Guibert, Sophie de; Maury, Sébastien; Cahn, Jean Yves; Socié, Gèrard

doi:10.1182/blood-2008-01-133918

Cited by 313 publications

(365 citation statements)

References 28 publications

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“…Consequently, treatment must continue indefinitely and leukopenia, thrombocytopenia, and reticulocytopenia, if present, persist. Treatment with eculizumab appears to have a favorable impact on survival, 31 because a recent study of 79 patients treated between 2002 and 2010 showed the same survival rates as those of age-and sex-matched controls from the general population. 29 The contribution of eculizumab to survival cannot be quantified accurately, however, because a control patient group was not included in that study.…”

Section: Classic Pnhmentioning

confidence: 99%

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

Parker

2011

Hematology

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Despite the availability of safe, effective targeted therapy that controls intravascular hemolysis, the management of paroxysmal nocturnal hemoglobinuria (PNH) remains complicated because of disease heterogeneity and close association with BM failure syndromes. The purpose of this review is to provide a framework for individualizing treatment based on disease classification. According to the recommendations of the International PNH Interest Group, patients can be placed into one of the following 3 categories: (1) classic PNH, (2) PNH in the setting of another BM failure syndrome, or (3) subclinical PNH. The PNH clone in patients with subclinical disease is insufficiently large to produce even biochemical evidence of hemolysis, and consequently, patients who fit into this category require no PNH-specific therapy. Patients with PNH in the setting of another BM failure syndrome (usually aplastic anemia or low-risk myelodysplastic syndrome) have at least biochemical evidence of hemolysis, but typically the PNH clone is small (Ͻ 10%) so that hemolysis does not contribute significantly to the underlying anemia. In these cases, the focus of treatment is on the BM failure component of the disease. Intravascular hemolysis is the dominant feature of classic PNH, and this process is blocked by the complement inhibitor eculizumab. The thrombophilia of PNH also appears to be ameliorated by eculizumab, but the drug has no effect on the BM failure component of the disease. Low-grade extravascular hemolysis due to complement C3 opsonization develops in most patients treated with eculizumab, and in some cases is a cause for suboptimal response to treatment. Allogeneic BM transplantation can cure classic PNH, but treatment-related toxicity suggests caution for this approach to management.

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Section: Classic Pnhmentioning

confidence: 99%

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

Parker

2011

Hematology

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“…27 AA and PNH are closely related conditions: AA may develop during the course of PNH and vice versa (AA/PNH syndrome), both being predisposed to AML and MDS. 28,29 Complication of clinically relevant PNH has been described in 15% to 25% of the patients with AA treated by IST. [30][31][32][33][34][35] Moreover, regardless of typical manifestations of PNH, GPI anchor-deficient, "PNH-type" cells are detectable at even higher frequencies (up to 67%) when assessed by sensitive flow cytometry using antibodies to CD55 or CD59 and/or fluorescent aerolysin (FLAER).…”

Section: Late Clonal Diseases In Aamentioning

confidence: 99%

Clonal hematopoiesis in acquired aplastic anemia

Ogawa

2016

Blood

162

130

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Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1. Mutations exhibit distinct chronological profiles and clinical impacts. BCOR/BCORL1 and PIGA mutations tend to disappear or show stable clone size and predict a better response to IST and a significantly better clinical outcome compared with mutations in DNMT3A, ASXL1, and other genes, which are likely to increase their clone size, are associated with a faster progression to MDS/AML, and predict an unfavorable survival. High frequency of 6pUPD and overrepresentation of PIGA and BCOR/BCORL1 mutations are unique to AA, suggesting the role of autoimmunity in clonal selection. By contrast, DNMT3A and ASXL1 mutations, also commonly seen in CH in the general population, indicate a close link to CH in the aged bone marrow, in terms of the mechanism for selection. Detection and close monitoring of somatic mutations/evolution may help with prediction and diagnosis of clonal evolution of MDS/AML and better management of patients with AA.

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“…The reported median survival with conventional treatment (red blood cell transfusions, steroids, androgens, growth factors, immunosuppressive therapy) is approximately ten years, ranging from a few months in patients with one or more risk factors (thrombocytopenia at diagnosis, progression to thrombocytopenia, development of thrombosis, pancytopenia, myelodysplasia or acute leukemia, age over 55 years) to many years in patients with no risk factors. [5][6][7] Unfortunately, risk factors have a limited role in predicting individual patient outcome, given that the natural history of paroxysmal nocturnal hemoglobinuria is widely heterogeneous.…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

Santarone¹,

Bacigalupo²,

Risitano³

et al. 2009

Haematologica

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BackgroundParoxysmal nocturnal hemoglobinuria is an acquired clonal disorder of the hemopoietic stem cells for which the only curative treatment is allogeneic hematopoietic stem cell transplantation. Design and MethodsThe aim of this retrospective study was to assess the long-term clinical and hematologic results in 26 paroxysmal nocturnal hemoglobinuria patients who received hematopoietic stem cell transplantation in Italy between 1988 and 2006. The patients were aged 22 to 60 years (median 32 years). Twenty-three donors were HLA-identical (22 siblings and one unrelated) and 3 were HLA-mismatched (2 related and one unrelated). ResultsFifteen patients received a myeloablative conditioning consisting of busulfan and cyclophosphamide (in all cases from identical donor) and 11 were given a reduced intensity conditioning (8 from identical donor and 3 from mismatched donor). The cumulative incidence of graft failure was 8% (4% primary and 4% secondary graft failure). Transplant-related mortality for all patients was 42% (26% and 63% for patients transplanted following myeloablative or reduced intensity conditioning, respectively). As of October 31, 2009, 15 patients (11 in the myeloablative conditioning group and 4 in the reduced intensity conditioning group) are alive with complete hematologic recovery and no evidence of paroxysmal nocturnal hemoglobinuria following a median follow-up of 131 months (range 30-240). The 10-year Kaplan-Meier probability of disease-free survival was 57% for all patients: 65% for 23 patients transplanted from identical donor and 73% for 15 patients transplanted with myeloablative conditioning. No thromboembolic event nor recurrence of the disease were reported following transplant. ConclusionsThe findings of this study confirm that most patients with paroxysmal nocturnal hemoglobinuria may be definitively cured with hematopoietic stem cell transplantation.Key words: paroxysmal nocturnal hemoglobinuria, hematopoietic stem cell transplantation, conditioning regimen. Haematologica 2010;95:983-988. doi:10.3324/haematol.2009 This is an open-access paper. Citation: Santarone S, Bacigalupo A, Risitano AM, Tagliaferri E, Di Bartolomeo E, Iori AP, Rambaldi A, Angelucci E, Spagnoli A, Papineschi F, Tamiazzo S, Di Nicola M, and Di Bartolomeo P. Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO). Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

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Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories

Cited by 313 publications

References 28 publications

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

Clonal hematopoiesis in acquired aplastic anemia

Hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria: long-term results of a retrospective study on behalf of the Gruppo Italiano Trapianto Midollo Osseo (GITMO)

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