Cancer Treatment Today » Hematology

Paroxysmal Nocturnal Hemoblobinuria(PNH) and Myelodysplastic syndromes: Treatment Approach – pro

M Levin, MD — Wed, 14 Nov 2012 15:35:33 +0000

It is rare to have MDS and PNH coexist as two full blown disorders but PNH clones can be present in MDS and PNH can resemble some features of MDS. Among acquired stem cell disorders, pathological links between myelodysplastic syndromes (MDS) and aplastic anaemia (AA), and paroxysmal nocturnal haemoglobinuria (PNH) and AA, have been often described, whereas the relationship between MDS and PNH is not entirely clear. Many reports identified small PNH clones in other stem cell failure syndromes, such as aplastic anemia or low-risk myelodysplastic syndrome have at least biochemical evidence of hemolysis, but typically the PNH clone is small (< 10%) so that hemolysis does not contribute significantly to the underlying anemia. Using high-sensitivity flow cytometry, approximately 60% of patients with aplastic anemia and 20% of patients with low-risk MDS have been found to have a detectable population of GPI-AP–deficient erythrocytes and granulocytes. 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(Soliris). When intravascular hemolysis is the predominant feature, treatment should be directed to the PNH component. The large majority of patients with PNH/AA and PNH/MDS have relatively small PNH clones (< 10%) and require no specific PNH therapy; in these cases, treatment should focus on the underlying BM failure syndrome(Parker et al).

Iwanaga M, Furukawa K, Amenomori T, Mori H, Nakamura H, Fuchigami K, Kamihira S, Nakakuma H, Tomonaga M. Paroxysmal nocturnal haemoglobinuria clones in patients with myelodysplastic syndromes.Br J Haematol. 1998 Jul;102(2):465-74.

Wang SA, Pozdnyakova O, Jorgensen JL, Medeiros LJ, Stachurski D, Anderson M, Raza A, Woda BA. Detection of paroxysmal nocturnal hemoglobinuria clones in patients with myelodysplastic syndromes and related bone marrow diseases, with emphasis on diagnostic pitfalls and caveats. Haematologica. 2009 Jan; 94(1):29-37.

Young NS. Paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes: clonal expansion of PIG-A-mutant hematopoietic cells in bone marrow failure.Haematologica. 2009 Jan;94(1):3-7.

Charles J. Parker, Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy ASH Education Book December 10, 2011 vol. 2011 no. 1 21-29
Fahri Sahin et al, Pesg PNH diagnosis, follow-up and treatment guidelines. Am J Blood Res. 2016; 6(2): 19–27.

For Lay version see here

Exjade for transfusion iron overload and thalassemia – pro

M Levin, MD — Fri, 07 Sep 2012 03:43:25 +0000

Iron overload is a cumulative, potentially life-threatening, consequence of frequent blood transfusions or conditions such as thalassemia. Iron starts to build up in the body after as few as 10 transfusions because the body cannot remove it on its own. Iron chelation is the only effective drug treatment for transfusion-related iron overload. In thalassemia, ineffective erytrhopoieisis causes iron overload as well. In iron chelation, an agent binds to iron in the body and tissues and helps remove it through the urine and/or feces.

Exjade (deferasirox) is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. The FDA does not provide criteria for iorn overload but increased deposition in the organs is generally accepted to be iron overload. MRI si more senstive in identifying iron overload than iron studies.

Exjade is administered once-daily as a drink. Exjade was developed specifically to meet the high unmet medical need for iron chelation despite the availability of deferoxamine, the standard iron chelator used around the world. While effective, deferoxamine requires nightly infusions by needle and pump, often lasting eight to 12 hours per night for five to seven nights a week as long as the patient continues to receive blood transfusions or has excess iron within the body. As a result, many patients may have stopped or avoided iron chelation therapy, thus risking the toxic effects of iron overload. Due to the burdensome administration of deferoxamine, compliance with standard chelation therapy is poor. Previous studies of patients with thalassemia have shown that good compliance with deferoxamine improves survival and quality of life.

Iron overload secondary to thalassemia also responds to Exjade. A phase III trial in thalassemia major patients demonstrated non-inferiority to deferoxamine at doses of over 20 mg/kg/day. Non-inferiority at lower doses of deferasirox was not established but this may have been solely due to study design. Therefore, in thalassemia, the optimal dose of deferasirox still need to be clarified.
A randomized, open-label, Phase III trial evaluated Patient-Reported Outcomes (PROs) at the end of one year and found that significantly more patients on deferasirox as compared to those on deferoxamine reported treatment satisfaction (89% vs. 41%, respectively) and treatment convenience (93% vs. 11%).65 Of those previously treated with deferoxamine, 97% of those in the deferasirox arm indicated a preference for deferasirox and 86% indicated a willingness to continue treatment as compared to 14% of those assigned to the deferoxamine group. These findings suggest that patients are generally compliant with Exjade therapy.

Another large study, was THALASSA, the first pivotal placebo-controlled studythat examined the benefit of iron chelation with Exjade® (deferasirox) in patients with non-transfusion-dependent thalassemia (NTDT), and it demonstrated that Exjade can significantly reduce iron overload.

Jadenu is the same drug as Exjade. indicated for treatment of chronic iron overload caused by nontransfusion-dependent thalassemia syndromes and with a liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight (dw) and a serum ferritin >300 mcg/L

Vichinsky E, Bernaudin F, Forni GL, Gardner R, Hassell K, Heeney MM, Inusa B, Kutlar A, Lane P, Mathias L, Porter J, Tebbi C, Wilson F, Griffel L, Deng W, Giannone V, Coates T.Long-term safety and efficacy of deferasirox (Exjade) for up to 5 years in transfusional iron-overloaded patients with sickle cell disease.Br J Haematol. 2011 Aug;154(3):387-97. doi: 10.1111/j.1365-2141.2011

ALSCT for MF – pro

M Levin, MD — Fri, 07 Sep 2012 03:42:17 +0000

Idiopathic myelofibrosis (IMF; also referred to as agnogenic myeloid metaplasia or myelosclerosis with myeloid metaplasia) is a chronic myeloproliferative disorder characterized by bone marrow fibrosis secondary to cytokine release from a clonal proliferation of hematopoietic stem cells and resulting in extramedullary hemopoiesis. Myeloablative allogeneic stem cell transplantation (allo-SCT) is the only curative treatment for myelofibrosis, although it is associated with high transplant-related mortality (TRM), particularly in the elderly, making most patients with IMF ineligible for this treatment.

The results of published studies strongly support allo-SCT as an effective treatment strategy in patients with IMF, indicating that it has moved from the experimental setting into that of a practical therapeutic option. Despite the potential for cure, the use of myeloablative protocols is hampered by the advanced age of most patients at diagnosis, and the high TRM associated with this procedure. Based on the available evidence, myeloablative transplantation should only be considered for younger patients.

The NCI lists allogeneic transplantation as an option for this disease. The literature generally supports it for patients with a better prognosis, earlier disease and better performance status.

Mesa RA, Barosi G, Cervantes F, Reilly JT, Tefferi A. Myelofibrosis with myeloid metaplasia: disease overview and non-transplant treatment options.Best Pract Res Clin Haematol. 2006;19(3):495-517.

Mesa RA.Myelofibrosis with myeloid metaplasia: therapeutic options in 2003.Curr Hematol Rep. 2003 May;2(3):264-70.

n p>Deeg HJ, Guardiola P. Allogeneic hemopoietic stem cell transplantation in patients with myelodysplastic syndrome or myelofibrosis. Int J Hematol. 2002;76 Suppl 2:29-34.

S G Papageorgiou, A Castleton, A Bloor and P D Kottaridis
Allogeneic stem cell transplantation as treatment for myelofibrosis Bone Marrow Transplantation (2006) 38, 721–727.

Arixtra and Leiden – pro

M Levin, MD — Fri, 07 Sep 2012 03:41:02 +0000

Factor V Leiden, or factor V G1691A, is a single-point mutation in the gene that codes for coagulation factor V.2 It involves a G (guanine)-to-A (adenine) substitution at nucleotide 1691 (G1691A) in exon 10, which predicts the replacement of arginine at amino acid residue 506 by glutamine (Arg506Gln). The mutation, transmitted through autosomal dominant inheritance, renders factor V resistant to inactivation by APC (a natural anticoagulant protein). Factor V Leiden accounts for 92% of cases of APC resistance (APC-R), with the remaining 8% of cases resulting from pregnancy, oral contraceptive use, cancer, selected APA, and other factor V point mutations. It is a well accepted indication for life-long anti-coagulation after a DVT or PE.

Low molecular weight heparin (LMWH) is an anticoagulant drug used in both the prevention of clot formation in the blood vessels (thrombosis) and in the treatment of conditions caused by clot formation or embolization. It is an injectable drug that may be administered by the patient or by a health care practitioner. LMWH may be used in some circumstances as an alternative to oral warfarin or injectable unfractionated heparin therapy (UFH). Fondaparinux (Arixtra®) is a synthetic pentasaccharide selective inhibitor of factor Xa used in a similar fashion and for some similar indications as LMWHs.

An extensive literature review and evaluation of the evidence regarding the use of LMWH, fondaparinux and other forms of antithrombotic therapy and prophylaxis was conducted by the Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy and published in “Chest” in September, 2004.

Fondaparinux (Arixtra®), is a factor Xa inhibitor with some similar indications and activity as the LMWHs. It may in some cases be used as an alternative to LMWHs for certain indications. Despite the fact LMWH has different indications and dosing regimens, and has been studied for different uses, there is considerable overlap for use in similar clinical circumstances as an alternative to UFH. When there is a choice between long term UFH and LMWH/fondaparinux, LMWH/fondaparinux has advantages in terms of frequency of administration, predictability of response, and decreased incidence of complications such as osteoporosis or heparin induced thrombocytopenia. Given these two options, it is reasonable that LMWH/fondaparinux would be the drug(s) of choice.

ANTITHROMBOTIC THERAPY AND PREVENTION OF THROMBOSIS, 9TH ED: AMERICAN COLLEGE OF CHEST PHYSICIANS EVIDENCE-BASED CLINICAL PRACTICE GUIDELINES

Chest February 2012 141:2 suppl 1S;

David Bergqvist Review of fondaparinux sodium injection for the prevention of venous thromboembolism in patients undergoing surgery. Vasc Health Risk Manag. 2006 ;2 (4):365-70

Colleen M. Johnson, MD Hypercoagulable States: A Review Vascular and Endovascular Surgery, Vol. 39, No. 2, 123-133 (2005)

Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344:1222-1231.

Novoseven off-label – pro

M Levin, MD — Fri, 07 Sep 2012 03:39:33 +0000

Recombinant activated factor seven (VIIa) is a vitamin K-dependent glycoprotein that is structurally similar to human plasma-derived factor VIIa. It has received approval from the Food and Drug Administration (FDA) for the treatment of bleeding episodes in patients with hemophilia A or B who have developed inhibitors to factor VIII or factor IX, respectively. It has recently been approved in the EU for Glantzman’s thromabasthenia. However, because of its effectiveness in pro-coagulation, it can potentially be used for a wide variety of bleeding situations. Coupled with its high cost, this caused a need for standards. The unlabeled uses of factor VIIa (recombinant) are constrained by high costs and limited clinical efficacy data. Currently, there are no national guidelines for the unlabeled indications of factor VIIa (recombinant); many institutions have written and follow their own institutional guidelines. Because of the lack of data, the approach of setting up intitutional gatekeepers to evaluate specific cases, has become widespread. Usually, an expert in each of the specialties of trauma, neurosurgery, hepatology and hematology are appointed to approve use in specific cases.

According to the FDA, Novoseven has been linked to heart attacks, strokes, deaths, and other health complications in patients given the medicine for other types of out-of-control bleeding, such as cerebral hemorrhages. The drug has shown promise as a treatment for cerebral hemorrhages, which is a potentially deadly kind of stroke caused by bleeding in the brain. The majority of the reported complications associated with the drug involved off-label use, instances where the drug was used to treat a condition not specifically approved by the FDA. Novo Nordisk changed the warning in the package insert to include information on side-effects in patients who do not have hemophilia. Novo is currently conducting studies on the safety of the drug in such patients.

NovoSeven (coagulation factor VIIa [recombinant]) package insert. Princeton, NJ: Novo Nordisk; 2005 Jun.

Lam MS, Sims-McCallum RP. Recombinant factor VIIa in the treatment of nonhemophiliac bleeding. Ann Pharmacother. 2005; 39:885–91.

Friederich PW, Henny CP, Messelink EJ et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet. 2003; 361:201–5.

Celeste N. Rudisill; Rebecca H. Hockman; Kathlene A. Degregory; Alan H. Mutnick; Barbara Gail Macik Implementing Guidelines for the Institutional Use of Factor VIIa (Recombinant): A Multidisciplinary Solution Am J Health-Syst Pharm. 2006;63(17):1641-1646

IgG for CVI – pro

M Levin, MD — Fri, 07 Sep 2012 03:38:28 +0000

Common variable immune deficiency (CVID) is characterized by humoral immune deficiency with onset after 24 months of age and usually in young adulthood, resulting in increased susceptibility to infections and diminished responses to protein and polysaccharide vaccines. The most common infections are sinopulmonary and include Streptococcus pneumonia, Hemophilis influenza, Klebsiella pneumonia, and sometimes mycoplasma infections. Individuals may experience meningitis or other systemic bacterial infections, recurrent eye or skin infections, or gastrointestinal symptoms related to compromised immune/gut homeostasis, including chronic diarrhea, malabsorption, or bloating. They may also have abnormal T-cell function and immune dysregulation, including lymphoid hyperplasia, gastrointestinal inflammation, autoimmune phenomena, and susceptibility to malignancy, especially lymphomas.

Treatment for CVID includes starting immune globulin replacement therapy to provide protective antibodies as soon as possible, appropriate treatment with antibiotics, and treatment as appropriate for autoimmune phenomena. Administration of purified immune globulin is important in preventing the recurrent sinopulmonary infections associated with CVID. This can now be done via two routes: intravenously (i.e., IVIG) and subcutaneously. Generally, IVIG is dosed at 400 mg/kg every three to four weeks.
Subcutaneous administration of immunoglobulin can be done with a variety of dosing schedules to suit the preference of a patient, with the overall goal of administering a total of 400 mg/kg every three to four weeks. Prophylactic antibiotics may help prevent the recurrent sinopulmonary infections associated with CVID. The goal is to keep IgG levels above 500.

Di Renzo M, Pasqui AL, Auteri A. Common variable immunodeficiency: a review. Clin Exp Med. 2004. 3:211-7

Kokron CM, Errante PR, Barros MT, Baracho GV, Camargo MM, Kalil J, Rizzo LV. Clinical and laboratory aspects of common variable immunodeficiency. An Acad Bras Cienc. 2004. 76:707-26

Andres E, Limbach FX, Kurtz JE, et al: Primary humoral immunodeficiency (late-onset common variable immunodeficiency) with antinuclear antibodies and selective immunoglobulin deficiency. Am J Med 2001 Oct 15; 111(6): 489

Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R. New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin. Clin Exp Immunol. 2013 Nov;174(2):203-11.

Deane S, Selmi C, Naguwa SM, Teuber SS, Gershwin ME. Common variable immunodeficiency: etiological and treatment issues. Int Arch Allergy Immunol. 2009;150(4):311-24.

Soliris for PNH – pro

M Levin, MD — Fri, 07 Sep 2012 03:36:44 +0000

Soliris is the first therapy approved for paroxysmal nocturnal hemoglobinuria (PNH), a rare, disabling and life-threatening blood disorder defined by chronic red blood cell destruction, or hemolysis. Soliris is FDA indicated for the treatment of patients with PNH to reduce hemolysis and it was approved on March 16th of 2007.

Soliris has proven to be a safe and effective therapy for PNH in three multi-national clinical studies: TRIUMPH, a placebo-controlled 26 week Phase 3 study involving 87 PNH patients,(5) SHEPHERD, an open-label 52 week Phase 3 trial involving 97 PNH patients,(6) and E05-001, a long term extension study.(7) These studies showed that Soliris reduced hemolysis in every treated patient. Hemolysis was dramatically reduced from a baseline LDH of 2,032 U/L to 239 U/L at week 26 (p<0.001). The reductions in hemolysis occurred within one week of initiating treatment and were sustained for periods of up to 54 months with continued dosing of Soliris. The reduction in hemolysis expands the number of circulating PNH cells and, thereby, increases the hemoglobin level. Hemoglobin stabilization and the number of transfused packed red blood cell units, the pivotal study’s co-primary endpoints, were both achieved; half of the Soliris-treated patients achieved hemoglobin stabilization compared with none of the patients in the placebo group, the median number of transfusions was reduced from 10 units/patient to 0 units/patient, respectively (p < 0.001 in both cases). Soliris patients reported less fatigue and improved health-related quality of life. There were fewer thrombotic events with Soliris treatment than during the same period of time prior to treatment.

Total duration of treatment with Soliris has not been determined . In the HUS studies, patients were treated for median of 40 weeks, with some treated beyond 60 weeks. Etiological basis of disease in both HUS and PNH suggests that the treatment should be prolonged. Retrospective reviews of experience suggest improved survival for prolonged treatment and at this point results for treatment of longer than a year are beginning to be published.

Under the Food and Drug Administration Amendments Act of 2007, FDA has determined that a REMS is necessary for the benefits of Soliris to outweigh the risks of the product. The REMS will include a Medication Guide for patients and requires that all prescribers and patients enroll in a special program to track the long term safety of Soliris therapy.

A Risk Evaluation and Mitigation Strategy (REMS) is a strategy to manage known or potential serious risks associated with a drug product and is required by the Food and Drug Administration to ensure that the benefits of the drug outweigh its risks.

The goals of the Soliris REMS, the OneSource Safety Support Program, are:

To mitigate the occurrence and morbidity associated with meningococcal infections
To inform and educate Healthcare Professionals (HCP) and Patients (or Caregivers, or Legal Guardians) regarding:
- the increased risk of meningococcal infections with Soliris
- the early signs of invasive meningococcal infections, and
- the need for immediate medical evaluation of signs and symptoms consistent with possible meningococcal infections.

R. J. Kelly, A. Hill, L. M. Arnold, G. L. Brooksbank, S. J. Richards, M. Cullen, L. D. Mitchell, D. R. Cohen, W. M. Gregory, P. Hillmen. (2011) Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival. Blood 117:25, 6786-6792

Alexander Röth, Ulrich Dührsen. (2011) Treatment of paroxysmal nocturnal hemoglobinuria in the era of eculizumab. European Journal of Haematology 87:6, 473-479

Kate McKeage. (2011) Eculizumab. Drugs 71:17, 2327-2345

Young N, Antonioli E, Rotoli B, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in patients with paroxysmal nocturnal hemoglobinuria: SHEPHERD phase III clinical study results. Blood 2006; 108:971.

Hillmen P, Muus P, Duhrsen U, et al. The terminal complement inhibitor eculizumab reduces thrombosis in patients with paroxysmal nocturnal hemoglobinuria. Blood 2006; 108:123.

Soliris(TM) (eculizumab) prescribing information. Alexion Pharmaceuticals, Inc.

Revised 12/13/2011

Eythropietics for anemia of chronic disease – pro

M Levin, MD — Fri, 07 Sep 2012 03:35:42 +0000

Anemia of chronic disease, the anemia that is the second most prevalent after anemia caused by iron deficiency, occurs in patients with acute or chronic immune activation. The condition has thus been termed “anemia of inflammation” but in many cases no obvious inflammatory cause is apparent. It is imperative to rule out iron deficiency co-existisng with chronic disease but in the presence of chronic disease, iron studies are unreliable and a bone marrow or a prolonged therapeutic trial are required. Hypothyroidism also can cause anemia but the mechanism appears to be hemodilution.

Erytropoietin, and presumably darbepoietin is best studied in the anemia of chronic disease due to rheumatoid arthritis, where randomized studies confirm its effectiveness.

Peeters HR, JongenLavrencic M, Vreugdenhil G, et al. Effect of recombinant human erythropoietin on anaemia and disease activity in patients with rheumatoid arthritis and anaemia of chronic disease: a randomised placebo controlled double blind 52 week clinical trial. Ann Rheum Dis 2005;55:739-44

Peeters HRM, Jongen-Lavrencic M, Vreugdenhil G, Swaak AJG. Effect of recombinant human erythropoietin on anemia and disease activity in patients with rheumatoid arthritis and anemia of chronic disease: a randomised placebo-controlled double blind 52-weeks clinical trial. Ann Rheum Dis 1996;55:739-44

Kaltwasser JP, Kessler U, Gottschalk R, et al. Effect of recombinant human erythropoietin and intravenous iron on anemia and disease activity in rheumatoid arthritis. J Rheumatol 2001;28:2340-436

Cullis JO. Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol 2011; 154:289.

Gangat N, Wolanskyj AP. Anemia of chronic disease. Semin Hematol 2013; 50:232.
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Macciò A, Madeddu C, Gramignano G, et al. The role of inflammation, iron, and nutritional status in cancer-related anemia: results of a large, prospective, observational study. Haematologica 2015; 100:124.

FUO – pro

M Levin, MD — Fri, 07 Sep 2012 03:34:34 +0000

Fever of unknown origin (FUO) refers to the presence of a documented fever for a specified time, for which a cause has not been found after a basic medical evaluation. The classic criteria developed in 1961 included: temperature greater than 101°F (38.3°C), for at least three weeks, and inability to find a cause after one week of study. Within the past decade, a revision has been proposed that categorizes FUO into classic, hospital acquired FUO, FUO associated with low white blood counts, and HIV associated FUO (AIDS related). The most frequent cause of FUO is still infection, though the percentage has decreased in recent years. Tuberculosis remains an important cause, especially when it occurs outside the lungs. The decrease in infections as a cause of FUO is due in part to improved culture techniques. In addition, technological advances have made it easier to diagnose non-infectious causes. For example, tumors and autoimmune diseases in particular are now easier to diagnose. (An autoimmune disease is one that arises when the body tolerance for its own cell antigenic cell markers disappears.)
Few symptoms in medicine present such a diagnostic challenge as fever. Nonetheless, if a careful, logical, and thorough evaluation is performed, a diagnosis will be found in most cases. The patient’s past medical history as well as travel, social, and family history should be carefully searched for important clues.

Usually the first step is to search for an infectious cause. Skin and other screening tests for diseases such as tuberculosis, and examination of blood, urine, and stool, are generally indicated. Antibody levels to a number of infectious agents can be measured; if these are rising, they may point to an active infection.Various x-ray studies are also of value. In addition to standard examinations, recently developed radiological techniques using ultrasound, computed tomography scan (CT scan) and magnetic resonance imaging (MRI) scans are now available. These enable physicians to examine areas that were once accessible only through surgery. Furthermore, new studies using radioactive materials (nuclear medicine), can detect areas of infection and inflammation previously almost impossible to find, even with surgery.Biopsies of any suspicious areas found on an x-ray exam can be performed by either traditional or newer surgical techniques. Material obtained by biopsy is then examined by a pathologist to look for clues as to the cause of the fever. Evidence of infection, tumor or other diseases can be found in this way. Portions of the biopsy are also sent to the laboratory for culture in an attempt to grow and identify an infectious organism.Patients with HIV are an especially difficult problem, as they often suffer from many unusual infections. HIV itself is a potential cause of fever.

Tumor markers are not an accepted part of FUO workup. More recently, PET scan is being utilized to find the primary source of fever.

Bleeker-Rovers CP, van der Meer JW, Oyen WJ. Fever of unknown origin. Semin Nucl Med. Mar 2009;39(2):81-7. [Medline].

Hao R, Yuan L, Kan Y, Li C, Yang J. Diagnostic performance of 18F-FDG PET/CT in patients with fever of unknown origin: a meta-analysis. Nucl Med Commun. Apr 29 201

Knockaert DC, Vanderschueren S, Blockmans D. Fever of unknown origin in adults: 40 years on. J Intern Med 2003;253:263-75.

Hirschmann JV. Fever of unknown origin in adults. Clin Infect Dis 1997;24:291-300.

Soliris – pro

M Levin, MD — Fri, 07 Sep 2012 03:33:14 +0000

On Friday, March 16, 2007, the U.S. Food and Drug Administration (FDA) approved Soliris (eculizumab) for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), a disorder in which abnormal breakdown of red blood cells occurs. Made by Alexion Pharmaceuticals, Soliris does not cure the disease, but treats the breakdown of the blood cells. Soliris has proven to be a safe and effective therapy for PNH in three multi-national clinical studies.

Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, Roth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L

The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. The New England Journal of Medicine 2006 Sep 21;355(12):1233-43.

Hill, A Eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Clinical advances in hematology & oncology : H&O 2005 Nov;3(11):849-50.

Hill A, Hillmen P, Richards SJ, Elebute D, Marsh JC, Chan J, Mojcik CF, Rother RP Sustained response and long-term safety of eculizumab in paroxysmal nocturnal hemoglobinuria. Blood 2005 Oct 1;106(7):2559-65. Epub 2005 Jun 28.

Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. The New England Journal of Medicine 2004 Feb 5;350(6):552-9.