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Th e n e w e n g l a n d j o u r n a l o f medicine

A Promising New Treatment for Refractory Aplastic AnemiaDonald Metcalf, M.D.

Aplastic anemia is characterized by severe defi-ciencies in peripheral-blood platelets, white cells,and red cells. These defects in mature cells oc-cur because aplastic bone marrow contains se-verely reduced numbers of hematopoietic stemcells and their lineage-committed progenitor-cell

progeny. In rare instances, the disease is familial,but in the majority of acquired cases, the originof the disease is unclear, and the most favoredhypothesis is that acquired aplastic anemia maybe an immunologically mediated disease.1

The preferred treatment is immunotherapywith antithymocyte globulin plus cyclosporine.If this treatment proves ineffective, eligible pa-tients can undergo allogeneic bone marrowtransplantation. Although either treatment strat-egy can achieve long-term control of the dis-ease, a considerable fraction of patients havedisease that is refractory to these treatments.1,2For such patients, an alternative approach is ur-gently needed.

The clinical introduction of the specific blood-cell growth factors erythropoietin for redcells and granulocyte colony-stimulating factoror granulocytemacrophage colony-stimulatingfactor for granulocytes and macrophages raised the possibility of additional methods forstimulating cell production. Regrettably, the re-sults have been very disappointing,3 most likely

because of the low numbers of target stem cellsand progenitor cells available for stimulation bythese growth factors.

With the subsequent purification and massproduction of thrombopoietin the major selec-tive growth factor driving megakaryocytopoiesis hope was again raised that thrombopoietinwould prove to be of major value in this disease,at least as a stimulus for megakaryocyte andplatelet formation. Unfortunately, the recombi-

nant thrombopoietin under study elicited anti-bodies against host platelets, and its furtherclinical development was abandoned.

However, studies in mice began to show someunexpected f indings regarding thrombopoietin.In mice engineered to lack the receptor for

thrombopoietin (termed Mpl/ mice) there was,as expected, a selective major deficit in platelets,but these mice also had very low numbers ofhematopoietic stem cells, and the cells thatwere present functioned poorly when they wererequired to repopulate irradiated mice.4 Furtherstudies confirmed that the thrombopoietin-Mplsystem had important actions in the formationand function of hematopoietic stem cells andtheir capacity to produce committed progenitorcells in multiple lineages, even though the effectof its actions on maturing cells was restricted tothe megakaryocytic-platelet lineage.5 Paradoxi-cally, the loss of Mpl appeared to increase therate of cell division in stem cells, but with timethis increase exhausted the pool of these cells,leading to bone marrow aplasia.5

The clinical impasse with thrombopoietin ledmany investigators to attempt to develop pep-tide or nonpeptide agonists that were capable ofactivating the MPL-receptor chain and that pref-erably were nonantigenic and orally available. Atpresent, foremost among these agents is the non-

peptide eltrombopag, an orally delivered smallmolecule. Importantly, eltrombopag can bind toMPL in a region not occupied by thrombopoi-etin,6 and therefore it might be able to activatean abnormal MPL that previously was unable ei-ther to bind to thrombopoietin or to initiate cellresponses to thrombopoietin. Eltrombopag wasshown clinically to be an effective stimulus forplatelet formation in patients with idiopathicthrombocytopenic purpura.7 The agent has also

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proved to be of value in increasing plateletcounts in patients with cirrhosis due to hepatitisC, in whom low platelet counts had precludedinterferon treatment.

In this issue of the Journal, Olnes et al.8 reportthat in a recent clinical trial, 44% of patientswith refractory aplastic anemia had positive re-

sponses to eltrombopag in at least one lineage at12 weeks, with significantly reduced transfusionrequirements. If confirmed, the implication ofthese intriguing results is that in many patientswith aplastic anemia, the hematopoietic stem cellsand their progenitor-cell progeny may have ac-quired defective MPL receptors that are unre-sponsive to thrombopoietin but remain able to beactivated by eltrombopag. Of particular interestis a recent study in which patients with familialaplastic anemia were shown to have nonsensemutations in the MPL gene.9 Time will tell

whether the hematopoietic cells in other patientswith aplastic anemia will also prove to have de-fective MPL signaling.

Disclosure forms provided by the author are available with thefull text of this article at NEJM.org.

From the Walter and Eliza Hall Institute of Medical Research,

Parkville, VIC, Australia.

1. Young NS, Calado RT, Scheinberg P. Current concepts in thepathophysiology and treatment of aplastic anemia. Blood 2006;108:2509-19.2. Bacigalupo A. Treatment strategies for patients with severeaplastic anemia. Bone Marrow Transplant 2008;42:Suppl 1:S42-S44.

3. Gurion R, Gafter-Gvili A, Paul M, et al. Hematopoieticgrowth factors in aplastic anemia patients treated with immu-nosuppressive therapy systematic review and meta-analysis.Haematologica 2009;94:712-9.4. Kimura S, Roberts AW, Metcalf D, Alexander WS. Hemato-poietic stem cell def iciencies in mice lacking c-Mpl, the receptorfor thrombopoietin. Proc Natl Acad Sci U S A 1998;95:1195-200.5. de Graaf CA, Metcalf D. Thrombopoietin and hematopoieticstem cel ls. Cell Cycle 2011;10:1582-9.6. Erickson-Miller CL, Delorme E, Tian SS, et al. Preclinicalactivity of eltrombopag (SB-497115), an oral, nonpeptide throm-bopoietin receptor agonist. Stem Cel ls 2009;27:424-30.7. Bussel JB, Cheng G, Saleh MN, et al. Eltrombopag for thetreatment of chronic idiopathic thrombocytopenic purpura.N Engl J Med 2007;357:2237-47.8. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and

improved hematopoiesis in refractory aplastic anemia. N Engl JMed 2012;367:11-9.9. Walne AJ, Dokal A, Plagnol V, et al. Exome sequencing iden-tifies MPL as a causative gene in familial aplastic anemia. Hae-matologica 2012;97:524-8.

DOI: 10.1056/NEJMe1204395Copyright 2012 Massachusetts Medical Societ y.

Improving the Estimating Equation for GFR A ClinicalPerspective

Matthew R. Weir, M.D.

In this issue of the Journal, Inker et al.1 describea new, combined creatininecystatin C estimat-ing equation that provides greater precision andaccuracy for classification of the glomerular fil-tration rate (GFR). This important step forwardto enhance accuracy takes advantage of bothcreatinine-based and cystatin Cbased equations.The cystatin Cbased equation has an advantageover the creatinine-based equation in that it is less

strongly affected by age, sex, and race. Of note,when cystatin C is incorporated into the newequation, race a variable that is frequentlylacking in laboratory and administrative data-bases will not be required for interpreting theresult. The new equation also improves accuracyfor a broader range of body-mass index (theweight in kilograms divided by the square of theheight in meters), especially among people withan index less than 20, for whom creatinine-

based GFR estimates are acknowledged to beless accurate.

The authors provide appropriate descriptionsof the limitations of this new formula. They wereconstrained in its development by the popula-tions of patients available in the studies inwhich both creatinine-based and cystatin Cbased estimates were contrasted with measuredGFR. Thus, there were fewer malnourished peo-

ple or ethnic minorities in their samples. In ad-dition, there were limited measurements ofmuscle mass, and little was known about medi-cations that could affect GFR.

What does this new GFR estimating equationbring to clinical care and outcomes? Late refer-rals for the management of chronic kidney dis-ease may result in suboptimal outcomes relatedto increased mortality, higher rates of hospital-ization, decreased rates of kidney transplanta-

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