Publications by authors named "Austin G Kulasekararaj"

52 Publications

Human Erythroid Progenitors Are Directly Infected by SARS-CoV-2: Implications for Emerging Erythropoiesis in Severe COVID-19 Patients.

Stem Cell Reports 2021 Feb 5. Epub 2021 Feb 5.

Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. Electronic address:

We document here that intensive care COVID-19 patients suffer a profound decline in hemoglobin levels but show an increase of circulating nucleated red cells, suggesting that SARS-CoV-2 infection either directly or indirectly induces stress erythropoiesis. We show that ACE2 expression peaks during erythropoiesis and renders erythroid progenitors vulnerable to infection by SARS-CoV-2. Early erythroid progenitors, defined as CD34CD117CD71CD235a, show the highest levels of ACE2 and constitute the primary target cell to be infected during erythropoiesis. SARS-CoV-2 causes the expansion of colony formation by erythroid progenitors and can be detected in these cells after 2 weeks of the initial infection. Our findings constitute the first report of SARS-CoV-2 infectivity in erythroid progenitor cells and can contribute to understanding both the clinical symptoms of severe COVID-19 patients and how the virus can spread through the circulation to produce local inflammation in tissues, including the bone marrow.
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http://dx.doi.org/10.1016/j.stemcr.2021.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862909PMC
February 2021

One-year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab.

Eur J Haematol 2021 Mar 3;106(3):389-397. Epub 2021 Jan 3.

Bone Marrow Transplantation Unit, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Ravulizumab every 8 weeks showed non-inferiority to eculizumab every 2 weeks in a 26-week, phase 3, randomized controlled trial in adults with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on eculizumab (NCT03056040). We report results from the first 26 weeks of the extension period in which patients continued ravulizumab (n = 96) or switched from eculizumab to ravulizumab (n = 95). At week 52, mean (SD) lactate dehydrogenase levels increased 8.8% (29%) with ravulizumab-ravulizumab and 5.8% (27%) with eculizumab-ravulizumab from primary evaluation period baseline. During the extension period, four patients (ravulizumab-ravulizumab, n = 3; eculizumab-ravulizumab, n = 1) experienced breakthrough hemolysis, but none associated with serum free C5 ≥ 0.5 μg/mL. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores remained stable through week 52. During the extension period, proportions of patients avoiding transfusion remained stable (ravulizumab-ravulizumab, 86.5%; eculizumab-ravulizumab, 83.2%); 81.2% and 81.1%, respectively, had stabilized hemoglobin. All patients maintained serum free C5 levels < 0.5 μg/mL. Adverse events were generally similar between groups, and rates were lower in the extension period. Adults with PNH on stable eculizumab therapy who received ravulizumab over 52 weeks experienced durable efficacy, with consistent efficacy in patients who received eculizumab during the primary evaluation period and then switched to ravulizumab. Ravulizumab was well tolerated.
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http://dx.doi.org/10.1111/ejh.13564DOI Listing
March 2021

Romiplostim in aplastic anaemia - another tool in the armamentarium.

Br J Haematol 2021 Jan 5;192(1):15-16. Epub 2020 Nov 5.

King's College Hospital NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/bjh.17189DOI Listing
January 2021

Danicopan: an oral complement factor D inhibitor for paroxysmal nocturnal hemoglobinuria.

Haematologica 2020 10 29;Online ahead of print. Epub 2020 Oct 29.

University of Auckland, Auckland.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterised by complement-mediated intravascular hemolysis (IVH) due to absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D (FD) inhibitor. Therapeutic FD inhibition was designed to control IVH and prevent C3-mediated extravascular hemolysis (EVH). In this open-label, phase 2, dose-finding trial, 10 untreated hemolytic PNH patients received danicopan monotherapy (100-200 mg thrice daily). Endpoints included change in lactate dehydrogenase (LDH) at day 28 (primary) and day 84 and hemoglobin. Safety, pharmacokinetics/pharmacodynamics, and patient-reported outcomes were measured. Ten patients reached the primary endpoint; two later discontinued: one for a serious adverse event (elevated aspartate aminotransferase/alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. IVH was inhibited, demonstrated by mean decreased LDH (5.7 times upper limit of normal [ULN] at baseline vs 1.8 times ULN [day 28] and 2.2 times ULN [day 84]; both p.
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http://dx.doi.org/10.3324/haematol.2020.261826DOI Listing
October 2020

Patient preferences and quality of life implications of ravulizumab (every 8 weeks) and eculizumab (every 2 weeks) for the treatment of paroxysmal nocturnal hemoglobinuria.

PLoS One 2020 4;15(9):e0237497. Epub 2020 Sep 4.

Department of Medical Social Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, United States of America.

Background: Eculizumab has transformed management of paroxysmal nocturnal hemoglobinuria (PNH) since its approval. However, its biweekly dosing regimen remains a high treatment burden. Ravulizumab administered every 8 weeks demonstrated noninferiority to eculizumab in two phase 3 trials. In regions where two PNH treatment options are available, it is important to consider patient preference.

Objective: The aim of this study was to assess patient preference for ravulizumab or eculizumab.

Methods: Study 302s (ALXN1210-PNH-302s) enrolled PNH patients who participated in the extension period of phase 3 study ALXN1210-PNH-302. In the parent study, eculizumab-experienced adult PNH patients received ravulizumab or eculizumab during a 26-week primary evaluation period. All patients in the extension period received ravulizumab. In study 302s, patient treatment preference was evaluated using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). Of 98 patients, 95 completed PNH-PPQ© per protocol for analysis.

Results: Overall, 93% of patients preferred ravulizumab whereas 7% of patients either had no preference (6%) or preferred eculizumab (1%) (P < 0.001). For specific aspects of treatment, ravulizumab was preferred (in comparison to no preference or eculizumab) on infusion frequency (98% vs. 0% vs. 2%), ability to plan activities (98% vs. 0% vs. 2%), and overall quality of life (88% vs. 11% vs. 1%), among other aspects. Most participants selected frequency of infusions as the most important factor determining preference (43%), followed by overall quality of life (23%).

Conclusion: This study shows that a substantial proportion of patients preferred ravulizumab over eculizumab and provides an important patient perspective on PNH treatment when there is more than one treatment option.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237497PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473546PMC
October 2020

Beneficial effects of eculizumab regardless of prior transfusions or bone marrow disease: Results of the International Paroxysmal Nocturnal Hemoglobinuria Registry.

Eur J Haematol 2020 Nov 11;105(5):561-570. Epub 2020 Aug 11.

Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Objectives: To evaluate the effects of eculizumab on transfusions and thrombotic events (TEs) in patients with and without prior history of transfusion in the International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry.

Methods: Registry patients enrolled on or before January 1, 2018, initiated on eculizumab no more than 12 months prior to enrollment, having known transfusion status for the 12 months before eculizumab initiation, and ≥12 months of Registry follow-up after eculizumab initiation, were included.

Results: Eculizumab treatment was associated with a 50% reduction in transfusions in patients with a transfusion history (10.6 units/patient-year before eculizumab vs 5.4 after; P < .0001), with greater reduction observed in those with no history of bone marrow disease vs those with bone marrow disease. Mean lactate dehydrogenase levels decreased from a mean of 6.7 to 1.4 times the upper limit of normal (ULN) in patients with transfusion history and from 5.1 to 1.2 times ULN in those with no transfusion history. TE and major adverse vascular event rates also decreased by 70% in patients with and without history of transfusion.

Conclusions: The benefit of eculizumab therapy does not appear to be limited to any group defined by transfusion history or bone marrow disease history.
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http://dx.doi.org/10.1111/ejh.13485DOI Listing
November 2020

Regulatory cells in immune-mediated aplastic anaemia - not T but B.

Br J Haematol 2020 08 4;190(4):486-487. Epub 2020 Jun 4.

Department of Haematological Medicine, King's College Hospital, London, UK.

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http://dx.doi.org/10.1111/bjh.16713DOI Listing
August 2020

Secondary HLH is uncommon in severe COVID-19.

Br J Haematol 2020 09 10;190(5):e283-e285. Epub 2020 Aug 10.

Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/bjh.16934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307063PMC
September 2020

Terminal complement inhibition dampens the inflammation during COVID-19.

Br J Haematol 2020 08 28;190(3):e141-e143. Epub 2020 Jun 28.

Department of Haematological Medicine, King's College Hospital-NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/bjh.16916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300670PMC
August 2020

Pharmacokinetic and pharmacodynamic effects of ravulizumab and eculizumab on complement component 5 in adults with paroxysmal nocturnal haemoglobinuria: results of two phase 3 randomised, multicentre studies.

Br J Haematol 2020 Nov 24;191(3):476-485. Epub 2020 May 24.

Clinical Haematology at Peter MacCallum Cancer Centre, The Royal Melbourne Hospital and University of Melbourne, Melbourne, Australia.

Ravulizumab, a novel long-acting complement component 5 (C5) inhibitor administered every 8 weeks (q8w), was non-inferior to eculizumab for all efficacy outcomes in two randomised, open-label, phase 3 trials in C5 inhibitor-naïve (Study 301) and eculizumab-experienced (Study 302) adult patients with paroxysmal nocturnal haemoglobinuria (PNH). This pre-specified analysis characterised ravulizumab pharmacokinetics (PK), pharmacodynamics (PD; free C5 levels), and PD differences between medications (Study 301, n = 246; Study 302, n = 195). Ravulizumab PK parameters were determined using non-compartmental analysis. Serum free C5 was quantified with a Gyros-based fluorescence assay (ravulizumab) and an electrochemiluminescence ligand-binding assay (eculizumab). Ravulizumab PK parameters were numerically comparable in both studies; the median time to maximum concentrations ranged from 2·3 to 2·8 and 2·3 to 2·6 h in studies 301 and 302, respectively. Ravulizumab steady-state serum concentrations were achieved immediately after the first dose and sustained throughout treatment. For ravulizumab, the mean (SD) post hoc terminal elimination half-life was 49·7 (8·9) days. Serum free C5 concentrations <0·5 µg/ml were achieved after the first ravulizumab dose and sustained throughout treatment in both studies. In a minority of patients, free C5 concentrations <0·5 µg/ml were not consistently achieved with eculizumab in either study. Ravulizumab q8w was more consistent in providing immediate, complete, sustained C5 inhibition than eculizumab every-2-weeks in patients with PNH.
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http://dx.doi.org/10.1111/bjh.16711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687070PMC
November 2020

Impact of somatic mutations in myelodysplastic patients with isolated partial or total loss of chromosome 7.

Leukemia 2020 09 17;34(9):2441-2450. Epub 2020 Feb 17.

Department of Haematological Medicine, King's College Hospital, NHS Foundation Trust, London, UK.

Monosomy 7 [-7] and/or partial loss of chromosome 7 [del(7q)] are associated with poor and intermediate prognosis, respectively, in myelodysplastic syndromes (MDS), but somatic mutations may also play a key complementary role. We analyzed the impact on the outcomes of deep targeted mutational screening in 280 MDS patients with -7/del(7q) as isolated cytogenetic abnormality (86 with del(7q) and 194 with -7). Patients with del(7q) or -7 had similar demographic and disease-related characteristics. Somatic mutations were detected in 79% (93/117) of patients (82% in -7 and 73% in del(7q) group). Median number of mutations per patient was 2 (range 0-8). There was no difference in mutation frequency between the two groups. Patients harbouring ≥2 mutations had a worse outcome than patients with <2 or no mutations (leukaemic transformation at 24 months, 38% and 20%, respectively, p = 0.044). Untreated patients with del(7q) had better overall survival (OS) compared with -7 (median OS, 34 vs 17 months, p = 0.034). In multivariable analysis, blast count, TP53 mutations and number of mutations were independent predictors of OS, whereas the cytogenetic subgroups did not retain prognostic relevance. This study highlights the importance of mutational analysis in terms of prognosis in MDS patients with isolated -7 or del(7q).
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http://dx.doi.org/10.1038/s41375-020-0728-xDOI Listing
September 2020

Ravulizumab for the treatment of paroxysmal nocturnal hemoglobinuria.

Expert Opin Biol Ther 2020 03 14;20(3):227-237. Epub 2020 Feb 14.

Department of Haematological Medicine, King's College Hospital, NHS Foundation Trust and King's College, London, UK.

: Eculizumab, which is indicated to treat patients with paroxysmal nocturnal hemoglobinuria (PNH), is a life-changing, life-saving therapy that decreases intravascular hemolysis and thrombosis and improves survival. Some eculizumab-treated patients, however, experience breakthrough hemolysis; and overall, the burden of the treatment schedule (intravenous infusions every 2 weeks) is substantial. Ravulizumab is a long-acting, second-generation complement component 5 (C5) inhibitor that is administered intravenously every 8 weeks. It is approved in the United States (December 2018), Japan (June 2019), Europe (July 2019), and Canada and Brazil (September 2019).: This article reviews data presented in journal articles identified on Medline/PubMed, abstracts presented at hematology meetings, and information posted on ClinicalTrials.gov and Alexion.com. Emphasis is placed on the non-inferiority of ravulizumab compared to eculizumab and the advantages of the 8-week, weight-based, dosing regimen.: In phase 3 trials, ravulizumab has been shown to be as safe and efficacious as eculizumab, to be associated numerically with lower rates of breakthrough hemolysis ( for non-inferiority <0.0004), and to be preferred over eculizumab by most patients. Ravulizumab is likely to replace eculizumab as the first-line treatment for PNH both in patients who are naive to eculizumab treatment and in patients who are clinically stable on eculizumab.
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http://dx.doi.org/10.1080/14712598.2020.1725468DOI Listing
March 2020

Characterization of breakthrough hemolysis events observed in the phase 3 randomized studies of ravulizumab versus eculizumab in adults with paroxysmal nocturnal hemoglobinuria.

Haematologica 2021 01 1;106(1):230-237. Epub 2021 Jan 1.

German Red Cross Blood Transfusion Service, Baden-Wurttemberg-Hessen and University Hospital Ulm.

Eculizumab is first-line treatment for paroxysmal nocturnal hemoglobinuria (PNH); however, approximately 11%-27% of patients may experience breakthrough hemolysis (BTH) on approved doses of eculizumab. Ravulizumab, a new long-acting C5 inhibitor with a four-times longer mean half-life than eculizumab, provides immediate, complete, and sustained C5 inhibition over 8-week dosing intervals. In two phase 3 studies, ravulizumab was noninferior to eculizumab (Pinf ≤0.0004) for the BTH endpoint; fewer patients experienced BTH with ravulizumab versus eculizumab in both studies (301 [complement inhibitor-naive patients], 4.0% vs 10.7%; 302 [patients stabilized on eculizumab at baseline], 0% vs 5.1%). In the current analysis, patient-level data were evaluated to assess causes and clinical parameters associated with incidents of BTH reported during the 26-week treatment periods in the ravulizumab phase 3 PNH studies. Of the five BTH events occurring in ravulizumab-treated patients across the studies, none were temporally associated with suboptimal C5 inhibition (free C5 ≥0.5 μg/mL); four (80.0%) were temporally associated with complement-amplifying conditions (CACs). Of the 22 events occurring in eculizumab-treated patients, eleven were temporally associated with suboptimal C5 inhibition, including three events also associated with concomitant infection. Six events were associated with CACs only. Five events were unrelated to free C5 elevation or reported CACs. These results suggest that the immediate, complete, and sustained C5 inhibition achieved through weight-based dosing of ravulizumab reduces the risk of BTH by eliminating BTH associated with suboptimal C5 inhibition in patients with PNH. Clinicaltrials.gov identifiers: Study 301, NCT02946463; Study 302, NCT03056040.
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http://dx.doi.org/10.3324/haematol.2019.236877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776354PMC
January 2021

Second-Generation C5 Inhibitors for Paroxysmal Nocturnal Hemoglobinuria.

BioDrugs 2020 Apr;34(2):149-158

Department of Haematological Medicine, King's College Hospital, National Institute of Health Research/Wellcome King's Clinical Research Facility, London, SE5 9RS, UK.

The C5 targeting monoclonal antibody eculizumab has changed the natural history of paroxysmal nocturnal hemoglobinuria (PNH) in the last 10 years. However, some unmet clinical needs persist, including persistent anemia with some patients requiring transfusions, incomplete C5 inhibition with breakthrough hemolysis (because of pharmacokinetic or pharmacodynamic issues such as infections, as well as conditions increasing complement activity), the underlying bone marrow failure, and the significant burden on patient quality of life (intravenous route of administration and frequency of infusions). Moreover, a subclass of patients carries C5 polymorphisms resistant to eculizumab inhibition. Several second-generation C5 inhibitors are under active study to overcome unmet clinical needs with eculizumab. Current strategies encompass increasing drug half-life, developing small molecule inhibitors of C5, and exploring new routes of administration (including subcutaneous and oral agents). In this review, we summarize available data on second-generation C5 inhibitors in PNH, including novel monoclonal antibodies, a small interfering RNA, and small molecules.
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http://dx.doi.org/10.1007/s40259-019-00401-1DOI Listing
April 2020

Clinical, histopathological and molecular characterization of hypoplastic myelodysplastic syndrome.

Leukemia 2019 10 2;33(10):2495-2505. Epub 2019 Apr 2.

Department of Haematological Medicine, King's College Hospital, London, UK.

Diagnostic criteria for hypoplastic myelodysplasic syndrome (h-MDS) have not been clearly established, making the differential diagnosis from other bone marrow failure syndromes (BMF) challenging. In this study, we aimed to delineate clinical, histopathological, and molecular features of h-MDS, based on a large and well-annotated cohort of patients with bone marrow (BM) hypocellularity. The study included 534 consecutive adult patients with hypocellular BM (278 h-MDS and 136 aplastic anemia), and 727 with normo- or hypercellular MDS (n-MDS). Comparison of clinical features of patients with h-MDS as defined by BM cellularity ≤25% (n = 204) or reduced age-adjusted cellularity (n = 74) did not reveal significant differences. We developed a diagnostic score to discriminate h-MDS from non-malignant BMF based on histological and cytological variables with the highest specificity for MDS (h-score). The information from chromosomal abnormalities and somatic mutation patterns was then integrated into a cyto-histological/genetic score (hg-score). This score was able to segregate two groups of h-MDS with a significantly different risk of blast progression (P < 0.001). The integration of cyto-histological and genetic features in adult patients with hypocellular BM facilitated segregation into two distinct groups, one with clinical and genetic features highly consistent with myeloid neoplasm, and one with features more consistent with non-malignant BMF.
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http://dx.doi.org/10.1038/s41375-019-0457-1DOI Listing
October 2019

Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study.

Blood 2019 02 3;133(6):540-549. Epub 2018 Dec 3.

Bone Marrow Transplantation Unit, Saint Louis Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab ( < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.
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http://dx.doi.org/10.1182/blood-2018-09-876805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368201PMC
February 2019

Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies.

Blood Adv 2018 09;2(17):2176-2185

Department of Hematology, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.

Ravulizumab (ALXN1210), a humanized monoclonal antibody to complement component C5, was engineered from eculizumab to have a substantially longer terminal half-life, permitting longer dosing intervals for paroxysmal nocturnal hemoglobinuria (PNH) treatment. Two phase 1b/2 multicenter open-label studies evaluated efficacy and safety of multiple doses and regimens of ravulizumab in PNH patients naive to complement-inhibitor treatment. Patients in study 103 (n = 13) received ravulizumab 900 mg (lower trough exposure) or 1800 mg every 4 weeks (higher trough exposure); those in study 201 (n = 26) received 1000 mg every 4, 1600 mg every 6, 2400 mg every 8, or 5400 mg every 12 weeks. Trough exposure levels with study 201 dosing regimens were similar to the study 103 900-mg every-4-weeks regimen. Rapid sustained reduction of plasma lactate dehydrogenase (LDH) occurred across all cohorts (73%-90% at end point vs baseline). A greater proportion of patients had normalized LDH (<234 U/L) at least once from days 29 to 253 in the higher- (85.7%) vs lower-trough-exposure (50.0%-83.3%) cohorts; the weighted average of the proportion of instances of LDH normalization from days 29 to 253 was highest in higher- vs lower-trough-exposure cohorts (62.3% vs 31.4%-54.5%). No patients in the higher-trough-exposure cohort, but 1 to 2 patients in all lower-trough-exposure cohorts, experienced breakthrough hemolysis. Ravulizumab improved quality of life (QoL) measures in all cohorts. Two patients experienced meningococcal infections; both recovered and continued in the study. In summary, ravulizumab provided rapid and sustained reduction in complement-mediated hemolysis and improved QoL at dosing intervals up to 12 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02598583 (study 103) and NCT02605993 (study 201).
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http://dx.doi.org/10.1182/bloodadvances.2018020644DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6134221PMC
September 2018

Sideroblastic anemia with myopathy secondary to novel, pathogenic missense variants in the gene.

Haematologica 2018 12 5;103(12):e564-e566. Epub 2018 Jul 5.

Department of Haematological Medicine, King's College Hospital, London, UK

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http://dx.doi.org/10.3324/haematol.2018.194464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6269300PMC
December 2018

Heterozygous variants in bone marrow failure and myeloid neoplasms.

Blood Adv 2018 01 4;2(1):36-48. Epub 2018 Jan 4.

Department of Haematological Medicine, King's College Hospital, London, United Kingdom.

Biallelic germline mutations in (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying variants. Pathogenicity assessment of heterozygous variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.
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http://dx.doi.org/10.1182/bloodadvances.2017008110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761623PMC
January 2018

Prognostic impact of bone marrow fibrosis and dyserythropoiesis in autoimmune hemolytic anemia.

Am J Hematol 2018 08 10;93(4):E88-E91. Epub 2018 Jan 10.

Hematology Unit, IRCCS Ca' Granda Ospedale Maggiore Policlinico of Milan, Milan, Italy.

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http://dx.doi.org/10.1002/ajh.25020DOI Listing
August 2018

Integrative Genomics Identifies the Molecular Basis of Resistance to Azacitidine Therapy in Myelodysplastic Syndromes.

Cell Rep 2017 07;20(3):572-585

Adult Cancer Program, Lowy Cancer Research Centre, UNSW, Sydney, NSW 2052, Australia; Prince of Wales Clinical School, UNSW, Sydney, NSW 2052, Australia; Haematology Department, South Eastern Area Laboratory Services, Prince of Wales Hospital, Randwick, NSW 2031, Australia. Electronic address:

Myelodysplastic syndromes and chronic myelomonocytic leukemia are blood disorders characterized by ineffective hematopoiesis and progressive marrow failure that can transform into acute leukemia. The DNA methyltransferase inhibitor 5-azacytidine (AZA) is the most effective pharmacological option, but only ∼50% of patients respond. A response only manifests after many months of treatment and is transient. The reasons underlying AZA resistance are unknown, and few alternatives exist for non-responders. Here, we show that AZA responders have more hematopoietic progenitor cells (HPCs) in the cell cycle. Non-responder HPC quiescence is mediated by integrin α5 (ITGA5) signaling and their hematopoietic potential improved by combining AZA with an ITGA5 inhibitor. AZA response is associated with the induction of an inflammatory response in HPCs in vivo. By molecular bar coding and tracking individual clones, we found that, although AZA alters the sub-clonal contribution to different lineages, founder clones are not eliminated and continue to drive hematopoiesis even in complete responders.
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http://dx.doi.org/10.1016/j.celrep.2017.06.067DOI Listing
July 2017

Clonal dominance of PNH- another piece to the jigsaw.

Br J Haematol 2017 04 14;177(1):9-10. Epub 2017 Mar 14.

Department of Haematology, Kings College Hospital, London, UK.

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http://dx.doi.org/10.1111/bjh.14552DOI Listing
April 2017

Myelodysplastic syndrome can propagate from the multipotent progenitor compartment.

Haematologica 2017 01 6;102(1):e7-e10. Epub 2016 Oct 6.

Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, Department of Haematological Medicine, London, UK

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http://dx.doi.org/10.3324/haematol.2016.152520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5210239PMC
January 2017

RPL27A is a target of miR-595 and may contribute to the myelodysplastic phenotype through ribosomal dysgenesis.

Oncotarget 2016 Jul;7(30):47875-47890

Department of Haematological Medicine, King's College London School of Medicine, London, UK.

We investigated the functional consequences following deletion of a microRNA (miR) termed miR-595 which resides on chromosome 7q and is localised within one of the commonly deleted regions identified for Myelodysplasia (MDS) with monosomy 7 (-7)/isolated loss of 7q (7q-). We identified several targets for miR-595, including a large ribosomal subunit protein RPL27A. RPL27A downregulation induced p53 activation, apoptosis and inhibited proliferation. Moreover, p53-independent effects were additionally identified secondary to a reduction in the ribosome subunit 60s. We confirmed that RPL27A plays a pivotal role in the maintenance of nucleolar integrity and ribosomal synthesis/maturation. Of note, RPL27A overexpression, despite showing no significant effects on p53 mRNA levels, did in fact enhance cellular proliferation. In normal CD34+ cells, RPL27A knockdown preferentially blocked erythroid proliferation and differentiation. Lastly, we show that miR-595 expression appears significantly downregulated in the majority of primary samples derived from MDS patients with (-7)/(7q-), in association with RPL27A upregulation. This significant downregulation of miR-595 is also apparent when higher risk MDS cases are compared to lower risk cases. The potential clinical importance of these findings requires further validation.
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http://dx.doi.org/10.18632/oncotarget.10293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5216985PMC
July 2016

CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: a retrospective mutational analysis.

Lancet Haematol 2015 May 6;2(5):e212-21. Epub 2015 May 6.

Department of Haematological Medicine, King's College London School of Medicine, Rayne Institute, King's College London, London, UK; Department of Haematology, King's College Hospital, King's College London, London, UK. Electronic address:

Background: A mechanism for clonal growth advantage in isolated del(5q) disease remains elusive. CSNK1A1 resides on the critically deleted region, and deletion of this gene has been shown in mouse knockout and transplantation studies to produce some characteristics of bone marrow failure, including a proliferative advantage. We aimed to establish the frequency, nature, and clinical association of CSNK1A1 mutations in patients with myelodysplastic syndrome and associated myeloid neoplasms.

Methods: Between June 1, 2004, and May 31, 2014, in King's College (London, UK), we did whole-exome sequencing of five patients with isolated del(5q) followed by targeted screening for CSNK1A1 mutations and 20 myelodysplastic syndrome-associated mutations in 245 additional patients with myeloid neoplasms. All patients met present WHO diagnostic criteria for myelodysplastic syndrome and other related myeloid neoplasms.

Findings: 39 (16%) of 250 patients with myeloid neoplasms had isolated del(5q), of whom seven (18%) had CSNK1A1 mutations. All these mutations were missense and presented in a highly conserved region that is implicated in ATP catalysis. Serial sampling and response to lenalidomide treatment showed that CSNK1A1 mutations were highly associated with the del(5q) clone. Only one patient with a CSNK1A1 mutation showed complete cytogenetic response to lenalidomide. Four (57%) of the seven patients carrying a CSNK1A1 mutation showed disease progression coupled with an increase in mutant allele burden (all four were on lenalidomide). We detected coexisting myelodysplastic syndrome-related gene mutations in patients with CSNK1A1 mutations, including TP53.

Interpretation: Similar to the effect of TP53 mutations on progression of del(5q) abnormality, mutant CSNK1A1 also gives rise to a poor prognosis in del(5q) abnormality, for which a coupled increase in P53 activation is suggested. CSNK1A1 mutations in del(5q) disease are important in the context of therapeutic manipulation and need incorporation into future prospective studies.

Funding: Leukaemia and Lymphoma Research.
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http://dx.doi.org/10.1016/S2352-3026(15)00050-2DOI Listing
May 2015

Sweet spot for cyclophosphamide: a balancing act.

Lancet Haematol 2015 Sep 2;2(9):e350-1. Epub 2015 Sep 2.

Department of Haematological Medicine, Kings College Hospital and Kings College London, Denmark Hill, London SE5 9RS, UK.

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http://dx.doi.org/10.1016/S2352-3026(15)00158-1DOI Listing
September 2015

SF3B1 mutant MDS-initiating cells may arise from the haematopoietic stem cell compartment.

Nat Commun 2015 Dec 8;6:10004. Epub 2015 Dec 8.

Department of Haematological Medicine, King's College London School of Medicine, London SE5 9NU, UK.

Despite the recent evidence of the existence of myelodysplastic syndrome (MDS) stem cells in 5q-MDS patients, it is unclear whether haematopoietic stem cells (HSCs) could also be the initiating cells in other MDS subgroups. Here we demonstrate that SF3B1 mutation(s) in our cohort of MDS patients with ring sideroblasts can arise from CD34(+)CD38(-)CD45RA(-)CD90(+)CD49f(+) HSCs and is an initiating event in disease pathogenesis. Xenotransplantation of SF3B1 mutant HSCs leads to persistent long-term engraftment restricted to myeloid lineage. Moreover, genetically diverse evolving subclones of mutant SF3B1 exist in mice, indicating a branching multi-clonal as well as ancestral evolutionary paradigm. Subclonal evolution in mice is also seen in the clinical evolution in patients. Sequential sample analysis shows clonal evolution and selection of the malignant driving clone leading to AML transformation. In conclusion, our data show SF3B1 mutations can propagate from HSCs to myeloid progeny, therefore providing a therapeutic target.
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http://dx.doi.org/10.1038/ncomms10004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4686651PMC
December 2015