Minor PNH clones do not distinguish inherited bone marrow failure syndromes from immune-mediated aplastic anemia

Narita, Atsushi; Miwata, Shunsuke; Imaya, Masayuki; Tsumura, Yusuke; Yamamori, Ayako; Wakamatsu, Mitsuru; Hamada, Masanori; Taniguchi, Rieko; Muramatsu, Hideki; Takahashi, Yoshiyuki

doi:10.1182/bloodadvances.2021006044

Cited by 6 publications

(2 citation statements)

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“…(38) In our cohort of 87 cases with a GPI-negative clone, this is the only patient with a telomerase mutation in whom a PNH clone was detected by flow cytometry and sequencing, although others have demonstrated frequent minor PNH clones (<0,1%) in inherited marrow failure syndromes. (39) On the other hand, the patient had a germline TERT variant predicted to be deleterious in silico and located at the same codon as a previously reported variant predicted to be pathogenic and to reduce telomerase activity to 44%. (40) The patient also had a family history of idiopathy pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 77%

Effects of nandrolone decanoate on telomere length and clinical outcome in patients with telomeropathies: a prospective trial

et al. 2022

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Androgens have been reported to elongate telomeres in retrospective and prospective trials with patients with telomeropathies, mainly with bone marrow failure. In our single-arm prospective clinical trial, 17 patients with short telomeres and/or germline pathogenic variants in telomere-biology genes associated with at least one cytopenia and/or radiologic diagnosis of ILD were treated with 5 mg/kg of intramuscular nandrolone decanoate every 15 days for 2 years. Ten of 13 evaluable patients (77%) showed telomere elongation at 12 months by flow-FISH (average increase, 0.87 kb; 95% CI, 0.20-1.55 kb; p=0.01). At 24 months, all 10 evaluable patients showed telomere elongation (average increase, 0.49 kb; 95% CI, 0.24-1.23 kb; p=0.18). Hematologic response was achieved in 8/16 patients (50%) with marrow failure at 12 months, and in 10/16 patients (63%) at 24 months. Seven patients had ILD at baseline, and two and three had pulmonary response at 12 and 24 months, respectively. Two patients died due to pulmonary failure during treatment. In the remaining evaluable patients, the pulmonary function remained stable or improved, but showed consistent decline after cessation of treatment. Somatic mutations in myeloid neoplasm-related genes were present in a minority of patients and were mostly stable during drug treatment. The most common adverse events (AE) were elevations in liver function test levels in 88%, acne in 59%, and virilization in 59%. No AE grade ≥ 4 was observed. Our findings indicate that nandrolone decanoate elongates telomeres in patients with telomeropathies, which correlated with clinical improvement in some cases and tolerable adverse events. ClinicalTrials.gov Identifier: NCT02055456.

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Section: Discussionmentioning

confidence: 77%

Effects of nandrolone decanoate on telomere length and clinical outcome in patients with telomeropathies: a prospective trial

et al. 2022

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“…While useful sorting out patients according to clinical manifestations and symptoms with “classic,” primarily hemolytic PNH, the proposed terminology can be somewhat misleading especially when considering the PNH/AA group. Within this group one can find patients in which high sensitive flow cytometry identifies very small GPI‐deficient cell clones with (most likely but not exclusively 42 ) immune mediated AA but without any signs of hemolysis as well as patients with cytopenia and signs of hemolysis. In patients, in which hemolysis is not the key clinical feature, but marrow failure is prominent, physicians have to follow aplastic anemia therapy algorithms, especially in patients with (very) severe aplastic anemia 40,43 .…”

Section: Where We Come Frommentioning

confidence: 99%

Paroxysmal nocturnal hemoglobinuria: Where we stand

Panse

2023

American J Hematol

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For the last 20 years, therapy of paroxysmal nocturnal hemoglobinuria (PNH) relied-up until recently-on antibody based terminal complement inhibitionon. PNH pathophysiology-a mutational defect leading to partial or complete absence of complement-regulatory proteins on blood cells-leads to intravascular hemolysis and consequences such as thrombosis and other sequelae. A plethora of new drugs interfering with the proximal and terminal complement cascade are under recent development and the first "proof-of-pinciple" proximal complement inhibitor targeting C3 has been approved in 2021. "PNH: where we stand" will try to give a brief account on where we came from and where we stand focusing on approved therapeutic options. The associated improvements as well as potential consequences of actual and future treatments as well as their impact on the disease will continue to necessitate academic and scientific focus on improving treatment options as well as on side effects and outcomes relevant to individual patient lives and circumstances in order to develop effective, safe, and available treatment for all hemolytic PNH patients globally.Note: Due to space limitation the author mostly cites reviews and overviews, giving readers the chance to easily find continuative summaries of potentially interesting topics. He therefore does apologize

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