The vast majority of patients with acute myeloid leukemia (AML) achieve complete remission (CR) after standard induction chemotherapy. However, the majority subsequently relapse and die of the ...disease. A leukemia stem cell (LSC) paradigm has been invoked to explain this failure of CR to reliably translate into cure. Indeed, LSCs are highly enriched in CD34+CD38- leukemic cells that exhibit positive aldehyde dehydrogenase activity (ALDH+) on flow cytometry, these LSCs are resistant to currently existing treatments in AML such as cytarabine and anthracycline that, at the cost of great toxicity on normal cells, are highly active against the leukemic bulk, but spare the LSCs responsible for relapse. To try to combat the LSC population selectively, a well-characterized ALDH inhibitor by the trivial name of dimethyl ampal thiolester (DIMATE) was assessed on sorted CD34+CD38- subpopulations from AML patients and healthy patients. ALDH activity and cell viability were monitored by flow cytometry. From enzyme kinetic studies DIMATE is an active enzyme-dependent, competitive, irreversible inhibitor of ALDH1. On cells in culture, DIMATE is a powerful inhibitor of ALDHs 1 and 3, has a major cytotoxic activity on human AML cell lines. Moreover, DIMATE is highly active against leukemic populations enriched in LSCs, but, unlike conventional chemotherapy, DIMATE is not toxic for healthy hematopoietic stem cells which retained, after treatment, their self-renewing and multi-lineage differentiation capacity in immunodeficient mice, xenografted with human leukemic cells. DIMATE eradicates specifically human AML cells and spares healthy mouse hematologic cells.
Le purpura thrombotique thrombocytopénique auto-immun (PTTi) est une microangiopathie thrombotique rare et spontanément fatale caractérisé par un déficit sévère en ADAMTS13, enzyme qui clive les ...multimères de facteur Willebrand. Des connaissances récentes sur la physiopathologie du PTTi ont conduit au développement de nouvelles thérapies ciblant le remplacement de l’ADAMTS13, la production des anticorps anti-ADAMTS13, et les interactions entre le facteur Willebrand et les plaquettes. De nouvelles stratégies thérapeutiques maximalistes émergent basées sur une trithérapie. Si les échanges plasmatiques restent le traitement de référence de la phase aiguë, l’introduction de traitements immunosuppresseurs en première ligne, corticoïdes et rituximab, a permis de réduire les exacerbations et les rechutes mais sans améliorer significativement la survie. Le caplacizumab, un nanobody bivalent humanisé anti-facteur Willebrand, est sur le point de révolutionner le traitement de la phase aiguë. En inhibant l’interaction entre les multimères de facteur Willebrand et les plaquettes, le caplacizumab empêche l’adhésion des plaquettes, prévient la formation de nouveaux microthrombi et protège les organes contre l’ischémie. Son association précoce aux échanges plasmatiques et aux traitements immunosuppresseurs prévient les évolutions défavorables et allège la charge en soins. Soutenu par des dosages répétés de l’activité ADAMTS13, le rituximab prévient les rechutes des patients qui présentent un déficit persistent ou récurrent en ADAMTS13 en rémission clinique. Cette revue examine comment les avancées en termes de diagnostic et de thérapies ciblées modifient le paradigme de traitement actuel tant à la phase aiguë qu’à la phase de rémission et contribuent à améliorer de façon spectaculaire le pronostic du PTTi.
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening thrombotic microangiopathy characterized by severe deficiency of ADAMTS13, the enzyme that cleaves von Willebrand factor multimers. Recent insights into iTTP pathophysiology have led to the development of new therapies targeting ADAMTS13 replacement, anti-ADAMTS13 antibodies, and von Willebrand factor-platelet interactions. New maximalist therapeutic strategies are emerging based on triple therapy. While plasma exchange remains the cornerstone therapy of the acute phase, the introduction of front-line immunosuppressive treatments, corticosteroids and rituximab, has led to a reduction in exacerbations and relapses but without any significant improvement in survival. Caplacizumab, a bivalent humanized anti-von Willebrand factor nanobody, is poised to revolutionize the treatment of the acute phase. By inhibiting the interaction between von Willebrand factor multimers and platelets, caplacizumab prevents platelets adhesion, prevents the formation of new microthrombi and protects organs from ischemia. Its early combination with plasma exchange and immunosuppressive therapy prevents unfavorable outcomes and reduces the burden of care. Supported by repeated ADAMTS13 assays, rituximab prevents relapse in patients with persistent or recurrent ADAMTS13 deficiency in clinical remission. This review examines how advances in diagnostics and targeted therapies are changing the current treatment paradigm in both the acute and remission phases and are contributing to dramatically improve the iTTP prognosis.
Summary
Background
Autoimmune thrombotic thrombocytopenic purpura (AI‐TTP) is characterized by an excess of circulating ultralarge von Willebrand factor (VWF) caused by anti‐ADAMTS‐13 autoantibodies. ...Animal studies, however, have shown that endothelial cell activation may also be an important trigger of AI‐TTP.
Objectives
To prospectively study circulating biomarkers of endothelial lesion and activation, such as circulating endothelial cells (CECs), soluble P‐selectin (sP‐selectin), or VWF, and of endothelial repair, such as circulating progenitor cells (CPCs) and endothelial progenitor cells (EPCs), in AI‐TTP, in relation to disease severity and prognosis.
Results
Twenty‐two patients were included in this study. CEC (P < 0.01), VWF (P < 0.05) and sP‐selectin (P < 0.01) levels were significantly increased during crisis, and returned to baseline levels during remission. Both CEC (P < 0.05) and sP‐selectin (P < 0.05) levels were significantly higher in patients who died or developed neurologic sequelae. CPC levels were substantially increased during the acute phase of the disease (P < 0.001), and returned to baseline levels during remission. Among CPCs, EPC levels were also increased during crisis (P < 0.05) and significantly decreased during remission. Patients who received < 16 plasma exchanges (PEs) had significantly higher EPC counts (P < 0.05) than those who needed more numerous PEs to obtain remission, suggesting that initial EPC counts may be associated with faster endothelial repair.
Conclusion
The profile of circulating endothelial markers shows massive endothelial activation and repair/remodeling during AI‐TTP, and suggests that CECs and EPCs may be promising prognostic biomarkers of the disease.
Weekly phlebotomy schedule is commonly recommended to achieve iron depletion in hereditary hemochromatosis (HH). However, in patients with severe iron overload, more than 2 years may be required, ...leading to fatigue and lack of compliance. For more than 10 years, we have used erythrocytapheresis (EA) as an alternative treatment.
To assess the number of EA to achieve iron depletion and the duration of the iron depletion therapy as well of the tolerance, we retrospectively analysed the data of newly diagnosed hemochromatosis patients, homozygote for the C282Y mutation, followed in our department between 2001 and 2007. EA were performed using a discontinuous or a continuous flow cell separators. The protocol consisted in a bimonthly EA until normalisation of the serum ferritin, with the aim of reducing the patient's hematocrit between 32-35% at the end of each session. Then we performed monthly EA until complete desaturation, defined as serum ferritin concentration below 50 μg/L and transferrin saturation below 40%.
Thirty patients were included (23 male, mean age 52 years, range 25-78) and 625 procedures analyzed. The mean volume of removed erythrocytes in each procedure was 416.4 mL (range 150-948), which equals to 374 mg of removed iron. Iron depletion (ferritin < 50 μg/L) was achieved after 11 months with 20 sessions (range 14-78). No serious adverse reactions or citrate toxicity were observed during and after the apheresis procedures. No specific fatigue was reported during the iron depletion therapy. Patient compliance was 100%. Clinical improvement was noted in 12 out of 18 of symptomatic patients.
We conclude that HH patients treated with bimonthly EA achieved iron depletion in less than 1 year under good condition of tolerance. These data support the use of EA in patients with a severe iron overload, since it may reduce the number of the procedures as well as the duration of the iron depletion therapy.
Les saignées hebdomadaires de sang total, jusqu’à épuisement des réserves en fer, représentent le traitement de référence de l’hémochromatose génétique de type 1. Cependant, pour les patients les ...plus surchargés, la phase de déplétion peut être très longue, souvent supérieure à deux ans et génératrice de fatigue et d’un manque d’observance préjudiciables à la qualité de la prise en charge. Depuis plus de dix ans, nous pratiquons des érythraphérèses comme alternative aux saignées.
Afin d’évaluer le nombre de séances d’érythraphérèse, la durée de la phase de déplétion et la tolérance de la méthode, nous avons analysé rétrospectivement entre 2001 et 2007 les données informatisées des patients homozygotes pour la mutation C282Y, jamais traités auparavant. Les érythraphérèses ont été réalisées avec un séparateur de cellules à flux discontinu ou à flux continu. Le protocole comportait deux phases, une phase dite de normalisation qui consistait en une séance d’aphérèse tous les 15
jours jusqu’à normalisation de la ferritinémie, puis une phase de déplétion jusqu’à épuisement des réserves, pendant laquelle les séances étaient espacées à une fois par mois. Le but à chaque séance était d’abaisser l’hématocrite entre 32 et 35 %.
Trente patients ont été inclus et 625 procédures analysées. Le volume moyen prélevé à chaque séance était de 416,4
mL (extrêmes 150–948), soit 374
mg de fer. La phase de déplétion (ferritine
<
50
ng/mL) a duré 11 mois, nécessitant 20 séances en moyenne (extrêmes 14–78). Il n’y a pas eu d’effets indésirables graves ou de complications dues au citrate. L’observance a été de 100 %. Une amélioration des symptômes a été notée chez 12 des 18 patients symptomatiques.
Le traitement par érythraphérèse permet d’obtenir la déplétion en fer en moins d’un an, dans de bonnes conditions de tolérance. Son utilisation devrait être privilégiée chez les patients atteints d’hémochromatose de type 1 très surchargés en fer afin de réduire le nombre de séances et de raccourcir la phase de déplétion.
Weekly phlebotomy schedule is commonly recommended to achieve iron depletion in hereditary hemochromatosis (HH). However, in patients with severe iron overload, more than 2
years may be required, leading to fatigue and lack of compliance. For more than 10
years, we have used erythrocytapheresis (EA) as an alternative treatment.
To assess the number of EA to achieve iron depletion and the duration of the iron depletion therapy as well of the tolerance, we retrospectively analysed the data of newly diagnosed hemochromatosis patients, homozygote for the C282Y mutation, followed in our department between 2001 and 2007. EA were performed using a discontinuous or a continuous flow cell separators. The protocol consisted in a bimonthly EA until normalisation of the serum ferritin, with the aim of reducing the patient's hematocrit between 32–35% at the end of each session. Then we performed monthly EA until complete desaturation, defined as serum ferritin concentration below 50
μg/L and transferrin saturation below 40%.
Thirty patients were included (23 male, mean age 52
years, range 25–78) and 625 procedures analyzed. The mean volume of removed erythrocytes in each procedure was 416.4
mL (range 150–948), which equals to 374
mg of removed iron. Iron depletion (ferritin
<
50
μg/L) was achieved after 11
months with 20 sessions (range 14–78). No serious adverse reactions or citrate toxicity were observed during and after the apheresis procedures. No specific fatigue was reported during the iron depletion therapy. Patient compliance was 100%. Clinical improvement was noted in 12 out of 18 of symptomatic patients.
We conclude that HH patients treated with bimonthly EA achieved iron depletion in less than 1
year under good condition of tolerance. These data support the use of EA in patients with a severe iron overload, since it may reduce the number of the procedures as well as the duration of the iron depletion therapy.
Summary
Background
Cardiac involvement is a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). However, diagnosis remains underestimated and delayed, owing to ...subclinical injuries. Cardiac troponin‐I measurement (cTnI) on admission could improve the early diagnosis of cardiac involvement and have prognostic value.
Objectives
To assess the predictive value of cTnI in patients with TTP for death or refractoriness.
Patients/Methods
The study involved a prospective cohort of adult TTP patients with acquired severe ADAMTS‐13 deficiency (< 10%) and included in the registry of the French Reference Center for Thrombotic Microangiopathies. Centralized cTnI measurements were performed on frozen serum on admission.
Results
Between January 2003 and December 2011, 133 patients with TTP (mean age, 48 ± 17 years) had available cTnI measurements on admission. Thirty‐two patients (24%) had clinical and/or electrocardiogram features. Nineteen (14.3%) had cardiac symptoms, mainly congestive heart failure and myocardial infarction. Electrocardiogram changes, mainly repolarization disorders, were present in 13 cases. An increased cTnI level (> 0.1 μg L−1) was present in 78 patients (59%), of whom 46 (59%) had no clinical cardiac involvement. The main outcomes were death (25%) and refractoriness (17%). Age (P = 0.02) and cTnI level (P = 0.002) showed the greatest impact on survival. A cTnI level of > 0.25 μg L−1 was the only independent factor in predicting death (odds ratio OR 2.87; 95% confidence interval CI 1.13–7.22; P = 0.024) and/or refractoriness (OR 3.03; 95% CI 1.27–7.3; P = 0.01).
Conclusions
A CTnI level of > 0.25 μg L−1 at presentation in patients with TTP appears to be an independent factor associated with a three‐fold increase in the risk of death or refractoriness. Therefore, cTnI level should be considered as a prognostic indicator in patients diagnosed with TTP.
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