Peter Hillmen

Publications (78)707.18 Total impact

• Article: Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria.

  Peter Hillmen, Petra Muus, Alexander Röth, Modupe O Elebute, Antonio M Risitano, Hubert Schrezenmeier, Jeffrey Szer, Paul Browne, Jaroslaw P Maciejewski, Jörg Schubert, Alvaro Urbano-Ispizua, Carlos de Castro, Gérard Socié, Robert A Brodsky
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  ABSTRACT: Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long-term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TEs decreased by 81·8%, with 96·4% of patients remaining free of TEs. Patients also showed a time-dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival.
  British Journal of Haematology 04/2013; · 4.94 Impact Factor
• Article: Thrombosis in paroxysmal nocturnal hemoglobinuria.

  Anita Hill, Richard Kelly, Peter Hillmen
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  ABSTRACT: The most frequent and feared complication of paroxysmal nocturnal hemoglobinuria (PNH) is thrombosis. Recent research has demonstrated that the complement and coagulation systems are closely integrated with each influencing the activity of the other to the extent that thrombin itself has recently been shown to activate the alternative pathway of complement. This may explain some of the complexity of the thrombosis in PNH. In this review the recent changes in our understanding of the pathophysiology of thrombosis in PNH as well as the treatment of thrombosis will be discussed. Mechanisms explored include platelet activation, toxicity of free hemoglobin, nitric oxide depletion, absence of other GPI-linked proteins such as urokinase-type plasminogen activator receptor and endothelial dysfunction. Complement inhibition with eculizumab generally has a dramatic effect in PNH and has a major impact in the prevention of thrombosis as well as its management in this disease.
  Blood 04/2013; · 9.90 Impact Factor
• Article: Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia.

  David Oscier, Claire Dearden, Efrem Erem, Christopher Fegan, George Follows, Peter Hillmen, Tim Illidge, Estella Matutes, Don W Milligan, Andrew Pettitt, Anna Schuh, Jennifer Wimperis
  British Journal of Haematology 10/2012; · 4.94 Impact Factor
• Article: Cross-sectional validation study of patient-reported outcomes in patients with paroxysmal nocturnal haemoglobinuria.

  Ilene Weitz, Gabrielle Meyers, Thierry Lamy, Jean-Yves Cahn, Maria Teresa Uranga, José Antonio García Vela, Miguel A Sanz, Beth Severino, Richard J Kelly, Peter Hillmen, Anita Hill
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  ABSTRACT: BACKGROUND: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired, clonal haematopoietic 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.
  Internal Medicine Journal 08/2012; · 1.54 Impact Factor
• Article: Under-recognized complications in patients with paroxysmal nocturnal haemoglobinuria: raised pulmonary pressure and reduced right ventricular function.

  Anita Hill, Robert J Sapsford, Andrew Scally, Richard Kelly, Stephen J Richards, Gus Khurisgara, Mohan U Sivananthan, Peter Hillmen
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  ABSTRACT: Pulmonary hypertension is becoming a recognized complication of the hereditary and acquired haemolytic anaemias, associated with a poor prognosis. Recently we reported that patients with paroxysmal nocturnal haemoglobinuria (PNH) have high levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), a biomarker associated with both right and left ventricular dysfunction and cardiac dysfunction. In the current study we evaluated a cohort of patients (N = 29) with haemolytic PNH for elevated pulmonary artery systolic pressure and cardiac function by Doppler-echocardiography. Of the 29 patients, eight were further studied using cardiac magnetic resonance imaging (MRI), as well as two additional patients (number of patients studied using cardiac MRI = 10). Plasma from the first cohort (N = 29) demonstrated intravascular haemolysis associated with a 12-fold increase in median nitric oxide (NO) consumption when compared with healthy volunteers (P < 0·001). Doppler echocardiography demonstrated normal left ventricular function and elevated pulmonary artery systolic pressure in 41% of patients. Cardiac MRI from the second cohort (N = 10) demonstrated depressed right ventricular function in 80% of PNH patients tested, and 60% had findings suggestive of subclinical small pulmonary emboli. Together, these data suggest a high prevalence of haemolysis-associated NO scavenging, Doppler-estimated systolic pulmonary hypertension, and depressed right ventricular function in patients with PNH.
  British Journal of Haematology 05/2012; 158(3):409-14. · 4.94 Impact Factor
• Article: Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial.

  Andrew R Pettitt, Richard Jackson, Stacey Carruthers, James Dodd, Susanna Dodd, Melanie Oates, Gillian G Johnson, Anna Schuh, Estella Matutes, Claire E Dearden, [......], Anton Kruger, Julie Blundell, Samir Agrawal, David Allsup, Stephen Proctor, Earnest Heartin, David Oscier, Terry J Hamblin, Andrew Rawstron, Peter Hillmen
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  ABSTRACT: In chronic lymphocytic leukemia (CLL), TP53 deletion/mutation is strongly associated with an adverse outcome and resistance to chemotherapy-based treatment. In contrast, TP53 defects are not associated with resistance to the anti-CD52 monoclonal antibody alemtuzumab or methylprednisolone. In an attempt to improve the treatment of TP53-defective CLL, a multicenter phase II study was developed to evaluate alemtuzumab and methylprednisolone in combination. Thirty-nine patients with TP53-deleted CLL (17 untreated and 22 previously treated) received up to 16 weeks of treatment with alemtuzumab 30 mg three times a week and methylprednisolone 1.0 g/m(2) for five consecutive days every 4 weeks. Antimicrobial prophylaxis consisted of cotrimoxazole, itraconazole, and aciclovir (or valganciclovir for asymptomatic cytomegalovirus viremia). The primary end point was response as assigned by an end-point review committee. Secondary end points were safety, progression-free survival (PFS) and overall survival (OS). The overall response rate, complete response rate (including with incomplete marrow recovery), median PFS, and median OS were 85%, 36%, 11.8 months, and 23.5 months, respectively, in the entire cohort and 88%, 65%, 18.3 months, and 38.9 months, respectively, in previously untreated patients. Grade 3 to 4 hematologic and glucocorticoid-associated toxicity occurred in 67% and 23% of patients, respectively. Grade 3 to 4 infection occurred in 51% of the overall cohort and in 29% of patients less than 60 years of age. Treatment-related mortality was 5%. Alemtuzumab plus methypredisolone is the most effective induction regimen hitherto reported in TP53-deleted CLL. The risk of infection is age related and, in younger patients, seems only marginally higher than that associated with rituximab, fludarabine, and cyclophosphamide.
  Journal of Clinical Oncology 04/2012; 30(14):1647-55. · 18.37 Impact Factor
• Article: Lessons from an incidental diagnosis of paroxysmal nocturnal haemoglobinuria.

  Jecko Thachil, Tim Webster, Richard Kelly, Peter Hillmen, Vanessa Martlew, Anita Hill
  Annals of Hematology 11/2011; 91(6):975-6. · 2.62 Impact Factor
• Article: Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia.

  Clemens-Martin Wendtner, Peter Hillmen, Daruka Mahadevan, Andreas Bühler, Lutz Uharek, Steven Coutré, Olga Frankfurt, Adrian Bloor, Francesc Bosch, Richard R Furman, [......], David D Hurd, Mikkael A Sekeres, Alessandra Ferrajoli, Sheetal Shah, Jennie Zhang, Laure Moutouh-de Parseval, Michael Hallek, Nyla A Heerema, Stephan Stilgenbauer, Asher A Chanan-Khan
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  ABSTRACT: Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL.
  Leukemia & lymphoma 08/2011; 53(3):417-23. · 2.40 Impact Factor
• Article: Ofatumumab in advanced stage chronic lymphocytic leukaemia: results of the UK named patient compassionate use programme.

  Onima Chowdhury, Abraham Varghese, Jonathon Pattinson, P Carrington, Adrian Bloor, George A Follows, Peter Hillmen, Anna Schuh
  British Journal of Haematology 05/2011; 155(4):519-21. · 4.94 Impact Factor
• Article: Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival.

  Richard J Kelly, Anita Hill, Louise M Arnold, Gemma L Brooksbank, Stephen J Richards, Matthew Cullen, Lindsay D Mitchell, Dena R Cohen, Walter M Gregory, Peter Hillmen
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  ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder with increased mortality and morbidity resulting from intravascular hemolysis. Eculizumab, a monoclonal antibody against the complement protein 5, stops the intravascular hemolysis in PNH. We evaluated 79 consecutive patients treated with eculizumab in Leeds between May 2002 and July 2010. The survival of patients treated with eculizumab was not different from age- and sex-matched normal controls (P = .46) but was significantly better than 30 similar patients managed before eculizumab (P = .030). Three patients on eculizumab, all over 50 years old, died of causes unrelated to PNH. Twenty-one patients (27%) had a thrombosis before starting eculizumab (5.6 events per 100 patient-years) compared with 2 thromboses on eculizumab (0.8 events per 100 patient-years; P < .001). Twenty-one patients with no previous thrombosis discontinued warfarin on eculizumab with no thrombotic sequelae. Forty of 61 (66%) patients on eculizumab for more than 12 months achieved transfusion independence. The 12-month mean transfusion requirement reduced from 19.3 units before eculizumab to 5.0 units in the most recent 12 months on eculizumab (P < .001). Eculizumab dramatically alters the natural course of PNH, reducing symptoms and disease complications as well as improving survival to a similar level to that of the general population.
  Blood 04/2011; 117(25):6786-92. · 9.90 Impact Factor
• Article: A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated chronic lymphocytic leukaemia.

  Peter Hillmen, Dena R Cohen, Kim Cocks, Andrew Pettitt, Hazem A Sayala, Andy C Rawstron, Daniel B Kennedy, Christopher Fegan, Don W Milligan, John Radford, Jane Mercieca, Claire Dearden, Raphael Ezekwisili, Alexandra F Smith, Julia Brown, Gillian A Booth, Abraham M Varghese, Christopher Pocock
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  ABSTRACT: Combination fludarabine (F), cyclophosphamide (C) and rituximab (R) is the standard front-line therapy in chronic lymphocytic leukaemia (CLL), but appropriate treatment of relapsed/refractory CLL is less clear. Combined FC and mitoxantrone (M) has been reported to be effective in a single arm study, and rituximab when added to chemotherapy in CLL is synergistic. A randomized, two-stage, Phase II trial of FCM and FCM-R was conducted in relapsed CLL. The primary endpoint was response rate 2 months after therapy, assessed according to the 2008 International Workshop CLL criteria. In addition, minimal residual disease (MRD) in the marrow was studied 2 months after therapy, with MRD negativity defined as <0·01% CLL cells. Fifty-two patients were entered, 26 in each arm. The overall response rates to FCM and FCM-R were 58% and 65% respectively. Combined complete response (CR) and CR with incomplete marrow recovery [CR(i)] was 15% (95% confidence interval [CI]:4-35%) for FCM and 42% (95%CI:23-63%) for FCM-R, with eight patients achieving MRD negativity (3 FCM; 5 FCM-R). The toxicity of both regimens was acceptable. In conclusion, the addition of rituximab to FCM improves the response rates in relapsed CLL, resulting in more complete remissions and without additional safety concerns. Efficacy and safety should be fully tested in a randomized Phase III trial.
  British Journal of Haematology 03/2011; 152(5):570-8. · 4.94 Impact Factor
• Article: Paroxysmal nocturnal hemoglobinuria--hemolysis before and after eculizumab.

  Antonio M Risitano, Rosario Notaro, Lucio Luzzatto, Anita Hill, Richard Kelly, Peter Hillmen
  New England Journal of Medicine 12/2010; 363(23):2270-2. · 53.30 Impact Factor
• Article: A comparison of the efficacy and safety of oral and intravenous fludarabine in chronic lymphocytic leukemia in the LRF CLL4 trial.

  Claire E Dearden, Sue Richards, Monica Else, Daniel Catovsky, Peter Hillmen
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  ABSTRACT: BACKGROUND:: An oral formulation of fludarabine was introduced for use in chronic lymphocytic leukemia in 2001 following studies demonstrating the bioequivalence of a 40 mg/m(2) oral dose with a 25 mg/m(2) intravenous dose. We assessed retrospectively the efficacy of these two routes of administration in the LRF CLL4 trial. METHODS:: A total of 777 patients were randomized from 1999-2004 to receive fludarabine, alone or with cyclophosphamide, or chlorambucil. In 2001, a protocol amendment allowed the oral formulation. There were 117 assessable patients who received fludarabine intravenously and 252 who received it orally. A total of 387 patients given chlorambucil acted as a control group. RESULTS:: Patients given oral fludarabine were less likely to receive the full dose (P = .0004) and experienced more, predominantly gastrointestinal, toxicity. Progression-free survival (PFS) and overall survival were not affected by the route of administration (PFS hazard ratio, 1.10; 95% confidence interval, 0.87-1.40), but the overall rate of response to treatment appeared to be lower with the oral formulation (P = .003). However, patients recruited since 2001 were older (P = .03) and were more likely to have TP53 deletion, and response rates after 2001 were also lower in the chlorambucil group. After excluding patients with TP53 deletion, no significant difference in outcome was attributable to the route of administration. CONCLUSIONS:: Although the LRF CLL4 data suggest no important difference in the effectiveness of oral compared with intravenous fludarabine, randomized trials are needed to reliably evaluate this comparison, particularly in combination with rituximab. Meanwhile, it is important to monitor compliance and gastrointestinal side effects with the oral route and to switch to intravenous therapy if a reduced dose is being received. Cancer 2011. © 2010 American Cancer Society.
  Cancer 12/2010; · 4.77 Impact Factor
• Article: Response: Defining response criteria in CLL patients treated in clinical research trials.

  Michael Hallek, Bruce D Cheson, Daniel Catovsky, Federico Caligaris-Cappio, Guillaume Dighiero, Hartmut Döhner, Peter Hillmen, Michael J Keating, Emili Montserrat, Kanti R Rai, Thomas J Kipps
  Blood 09/2010; 116(10):1817-8. · 9.90 Impact Factor
• Article: Erratum: "Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinura" by Hillmen et al., Am J Hematol 553-559, 2010, DOI number 21757.

  Peter Hillmen, Modupe Elebute, Richard Kelly, Alvaro Urbano-Ispizua, Anita Hill, Russell P Rother, Gus Khursigara, Chieh-Lin Fu, Mitsuhiro Omine, Paul Browne, Wendell Rosse
  American Journal of Hematology 09/2010; · 4.67 Impact Factor
• Source

  Available from: peerproject.eu

  Article: Long-term effect of the complement inhibitor eculizumab on kidney function in patients with paroxysmal nocturnal hemoglobinuria.

  Peter Hillmen, Modupe Elebute, Richard Kelly, Alvaro Urbano-Ispizua, Anita Hill, Russell P Rother, Gus Khursigara, Chieh-Lin Fu, Mitsuhiro Omine, Paul Browne, Wendell Rosse
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  ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is a debilitating and life-threatening disease in which lysis of PNH red blood cells frequently manifests with chronic hemolysis, anemia, and thrombosis. Renal damage in PNH is associated with chronic hemosiderosis and/or microvascular thrombosis. We determined the incidence of renal dysfunction or damage, defined by stages of chronic kidney disease (CKD), in a large cohort of PNH patients and evaluated the safety and efficacy of the complement inhibitor eculizumab in altering its progression. Renal dysfunction or damage was observed in 65% of the study population at baseline with 21% of patients with later stage CKD or kidney failure (glomerular filtration rate [GFR] <or=60 ml/min/1.73 m(2); Stage 3, 4, or 5). Eculizumab treatment was safe and well-tolerated in patients with renal dysfunction or damage and resulted in the likelihood of improvement as defined as categorical reduction in CKD stage (P < 0.001) compared with baseline and to placebo (P = 0.04). Improvement in renal function was more commonly seen in patients with baseline CKD Stages 1-2 (67.1% improvement, P < 0.001) although improvement was also observed in patients with CKD Stages 3-4 (P = 0.05). Improvements occurred quickly and were sustained for at least 18 months of treatment. Patients categorized at CKD Stages 3-5 did not worsen during treatment with eculizumab. Overall, 40 (21%) of 195 patients who demonstrated renal dysfunction or damage at baseline were no longer classified as such after 18 months of treatment. Administration of eculizumab to patients with renal dysfunction or damage was well tolerated and was usually associated with clinical improvement.
  American Journal of Hematology 08/2010; 85(8):553-9. · 4.67 Impact Factor
• Article: Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia.

  William G Wierda, Thomas J Kipps, Jirí Mayer, Stephan Stilgenbauer, Cathy D Williams, Andrzej Hellmann, Tadeusz Robak, Richard R Furman, Peter Hillmen, Marek Trneny, Martin J S Dyer, Swami Padmanabhan, Magdalena Piotrowska, Tomas Kozak, Geoffrey Chan, Randy Davis, Nedjad Losic, Joris Wilms, Charlotte A Russell, Anders Osterborg
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  ABSTRACT: New treatments are needed for patients with fludarabine- and alemtuzumab-refractory (FA-ref) chronic lymphocytic leukemia (CLL) or patients with fludarabine-refractory CLL with bulky (> 5 cm) lymphadenopathy (BF-ref) who are less suitable for alemtuzumab treatment; these groups have poor outcomes with available salvage regimens. Ofatumumab (HuMax-CD20) is a human monoclonal antibody targeting a distinct small-loop epitope on the CD20 molecule. We conducted an international clinical study to evaluate the efficacy and safety of ofatumumab in patients with FA-ref and BF-ref CLL. Patients received eight weekly infusions of ofatumumab followed by four monthly infusions during a 24-week period (dose 1 = 300 mg; doses 2 to 12 = 2,000 mg); response by an independent review committee (1996 National Cancer Institute Working Group criteria) was assessed every 4 weeks until week 24 and then every 3 months until month 24. This planned interim analysis included 138 treated patients with FA-ref (n = 59) and BF-ref (n = 79) CLL. The overall response rates (primary end point) were 58% [corrected] and 47% in the FA-ref and BF-ref groups, respectively. Complete resolution of constitutional symptoms and improved performance status occurred in 57% and 48% of patients, respectively. Median progression-free survival and overall survival times were 5.7 and 13.7 months in the FA-ref group, respectively, and 5.9 and 15.4 months in the BF-ref group, respectively. The most common adverse events during treatment were infusion reactions and infections, which were primarily grade 1 or 2 events. Hematologic events during treatment included anemia and neutropenia. Ofatumumab is an active, well-tolerated treatment providing clear clinical improvements for fludarabine-refractory patients with very poor-prognosis CLL.
  Journal of Clinical Oncology 03/2010; 28(10):1749-55. · 18.37 Impact Factor
• Article: Effect of eculizumab on haemolysis-associated nitric oxide depletion, dyspnoea, and measures of pulmonary hypertension in patients with paroxysmal nocturnal haemoglobinuria.

  Anita Hill, Russell P Rother, Xunde Wang, Sidney M Morris, Kerry Quinn-Senger, Richard Kelly, Stephen J Richards, Monica Bessler, Leonard Bell, Peter Hillmen, Mark T Gladwin
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  ABSTRACT: Pulmonary hypertension (PH) is a common complication of haemolytic anaemia. Intravascular haemolysis leads to nitric oxide (NO) depletion, endothelial and smooth muscle dysregulation, and vasculopathy, characterized by progressive hypertension. PH has been reported in patients with paroxysmal nocturnal haemoglobinuria (PNH), a life-threatening haemolytic disease. We explored the relationship between haemolysis, systemic NO, arginine catabolism and measures of PH in 73 PNH patients enrolled in the placebo-controlled TRIUMPH (Transfusion Reduction Efficacy and Safety Clinical Investigation Using Eculizumab in Paroxysmal Nocturnal Haemoglobinuria) study. At baseline, intravascular haemolysis was associated with elevated NO consumption (P < 0.0001) and arginase-1 release (P < 0.0001). Almost half of the patients in the trial had elevated levels (> or =160 pg/ml) of N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of pulmonary vascular resistance and right ventricular dysfunction previously shown to indicate PH. Eculizumab treatment significantly reduced haemolysis (P < 0.001), NO depletion (P < 0.001), vasomotor tone (P < 0.05), dyspnoea (P = 0.006) and resulted in a 50% reduction in the proportion of patients with elevated NT-proBNP (P < 0.001) within 2 weeks of treatment. Importantly, the significant improvements in dyspnoea and NT-proBNP levels occurred without significant changes in anaemia. These data demonstrated that intravascular haemolysis in PNH produces a state of NO catabolism leading to signs of PH, including elevated NT pro-BNP and dyspnoea that are significantly improved by treatment with eculizumab.
  British Journal of Haematology 03/2010; 149(3):414-25. · 4.94 Impact Factor
• Article: Clinical and diagnostic implications of monoclonal B-cell lymphocytosis.

  Andy C Rawstron, Peter Hillmen
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  ABSTRACT: Monoclonal B-lymphocytosis (MBL) is defined as the presence of a population of monoclonal B-cells, usually with a chronic lymphocytic leukaemia (CLL) phenotype, which comprise fewer than 5000 cells per microl with no evidence of tissue involvement. Over the past few years, MBL has been clearly defined and differentiated from CLL so that individuals with MBL are no longer inappropriately labelled as suffering from leukaemia. In this review, we will describe the entity of MBL and summarise the evidence that underlies the current theory on the pathophysiology of the disorder, the relationship with CLL and the probability of developing progressive disease requiring treatment. In addition, we will evaluate the importance of further clinical investigations, in particular, the relevance of screening for MBL and undertaking bone marrow investigations according to the clinical setting and B-cell phenotype.
  Best practice & research. Clinical haematology 03/2010; 23(1):61-9. · 3.13 Impact Factor
• Article: Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization.

  Anita Hill, Russell P Rother, Louise Arnold, Richard Kelly, Matthew J Cullen, Stephen J Richards, Peter Hillmen
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  ABSTRACT: Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia characterized by intravascular hemolysis which has been demonstrated to be effectively controlled with eculizumab. However, lactate dehydrogenase levels remain slightly elevated and haptoglobin levels remain low in some patients suggesting residual low-level hemolysis. This may be due to C3-mediated clearance of paroxysmal nocturnal hemoglobinuria red blood cells through the reticuloendothelial system. Thirty-nine samples from patients not treated with eculizumab and 31 samples from patients treated with eculizumab were obtained (for 17 of these 31 samples there were also samples taken prior to eculizumab treatment). Membrane bound complement was assessed by flow cytometry. Direct antiglobulin testing was carried out using two methods. Lactate dehydrogenase was assayed to assess the degree of hemolysis. Three of 39 patients (8%) with paroxysmal nocturnal hemoglobinuria not on eculizumab had a positive direct antiglobulin test, while the test was positive in 21 of 31 (68%) during eculizumab treatment. Of these 21 patients who had a positive direct antiglobulin test during eculizumab treatment, 17 had been tested prior to treatment; only one was positive. Flow cytometry using anti-C3 monoclonal antibodies was performed on the 21 direct antiglobulin test-positive, eculizumab-treated patients; the median proportion of C3-positive total red blood cells was 26%. Among the eculizumab-treated patients, 16 of the 21 (76.2%) with a positive direct antiglobulin test received at least one transfusion compared with one of ten (10.0%) of those with a negative test (P<0.01). Among the eculizumab-treated patients, the mean hemoglobin value for the 21 with a positive direct antiglobulin test was 9.6+/-0.3 g/dL, whereas that in the ten patients with a negative test was 11.0+/-0.4 g/dL (P=0.02). These data demonstrate a previously masked mechanism of red cell clearance in paroxysmal nocturnal hemoglobinuria and suggests that blockade of complement at C5 allows C3 fragment accumulation on some paroxysmal nocturnal hemoglobinuria red cells, explaining the residual low-level hemolysis occurring in some eculizumab-treated patients.
  Haematologica 02/2010; 95(4):567-73. · 6.42 Impact Factor