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Hindawi Publishing CorporationClinical and Developmental ImmunologyVolume , Article ID ,pageshttp://dx.doi.org/.//

Review ArticleAutoimmune Cytopenias in Chronic Lymphocytic Leukemia

Giovanni DArena,1 Roberto Guariglia,1 Francesco La Rocca,2 Stefania Trino,2

Valentina Condelli,2 Laura De Martino,3Vincenzo De Feo,3 and Pellegrino Musto1

Onco-Hematology Department, IRCCS Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy Laboratory of Pre-clinical and Translational Research, IRCCS Centro di Riferimento Oncologico della Basilicata,

Rionero in Vulture, Italy Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Salerno, Italy

Correspondence should be addressed to Giovanni DArena; [email protected]

Received January ; Revised March ; Accepted March

Academic Editor: Regis Peffault De La our

Copyright Giovanni DArena et al. Tis is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Te clinical course o chronic lymphocytic leukemia (CLL) may be complicated at any time by autoimmune phenomena.Te mostcommon ones are hematologic disorders, such as autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (IP).Pure red cell aplasia (PRCA) and autoimmune agranulocytosis (AG) are, indeed, more rarely seen. However, they are probablyunderestimated due to the possible misleading presence o cytopenias secondary to leukemic bone marrow involvement or to

chemotherapy cytotoxicity. Te source o autoantibodies is still uncertain, despite the most convincing data are in avor o theinvolvement o resting normal B-cells. In general, excluding the specic treatment o underlying CLL, the managemento thesecomplications is notdifferent romthat o idiopathic autoimmune cytopenias or o thoseassociated to other causes. Among differenttherapeutic approaches, monoclonal antibody rituximab, given alone or in combination, has shown to be very effective.

1. Introduction

Autoimmune phenomena may complicate the clinical courseo chronic lymphocytic leukemia (CLL). Autoimmunecytopenias (AC) are much more common than other nonhematologic complications, sometimes representing therst appearance o the disease []. Te most requent

autoimmune disorder is hemolytic anemia (AIHA); immunethrombocytopenia (IP), pure red cell aplasia (PRCA) andautoimmune agranulocytosis (AG) are more rarely seen andprobably underestimated, being requently considered dueto disease inltration o bone marrow or as a consequenceo hematologic toxicity o chemotherapy []. Otherautoimmune diseases may be observed in CLL patients,such as bullous pemphigoid, allergic vasculitis, rheumatoidarthritis, systemic lupus erythematosus, ulcerative colitis[].

Te incidence o hemic autoimmune complications inCLL is quite different in studies published so ar. Tis isprobably due to the act that it is sometimes difficult to

understand the cause o cytopenias in these patients. Overall,the percentage o patients experiencing cytopenia duringthe course o the disease is estimated rom .% to .%[, ]. able summarizes the incidence o the hematologicalautoimmune disorders in CLL patients.

Among others, a large series o patients was reported byDuek et al. []. Tey analyzed patients rom the Israel

CLL Study Group, ollowed or years and ound casesshowing a single or a combination o autoimmune disorders.Among them, (.%) had AIHA at diagnosis, (%) had a direct antiglobulin test (DA)-positivity withoutclinical and laboratory evidence o AIHA at diagnosis, (.%) developed AIHA during the ollow-up ( ollowingudarabine therapy), had IP, two o whom being DA-positive also and classied as having Evans syndrome.

More recently, Moreno et al. analyzed Spanish CLLpatients ollowed or years, showing that (%) patientshad AC: (%) had AIHA, (%) had IP, and patient(.%) had Evans syndrome []. Zent and Kay analyzed thelargest series (, patients with CLL) ollowed or years
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Clinical and Developmental Immunology

: Reported incidenceo autoimmune cytopeniacomplicatingCLL.

Autoimmune cytopenia Incidence

AIHA [,] .%

IP [,,,] %

PRCA [,,,]

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: Immune deects in CLL.

-cell

Increased circulating number [,,,,]

Decresed CD/CD ratio [,]

T polarization [,,]

Impaired immunological synapse []

Increased circulating number o regs [,]B-cell

Hypogammaglobulinemia [,,]

Poor response to vaccination [,]

NK cell

Increased circulating number []

Reduced killing activity [,]

Lack o granules []

Neutrophils

Reduced phagocytic and bactericidal unction [,,]

Abnormal migration and chemotaxis []

remains still unknown. Chiorazzi and Ferrarini suggestedthat CLL may derive rom marginal zone B-cell clonalexpansion []. Human B- cells have been recently alsoidentied and proposed to originate CLL[,]. Tis smallsubset o B-cells constitutively produces antibodies and hasbeen connected to autoimmune disorders. Immature B-cellsleaving the bone marrow to reach the splenic microenviron-ment and completing their maturation process need to passthrough transitional stages, and, thereore, they are calledtransitional B cells []. All these cells can be positivelyselected by autoantigen reactivity. However, only a minorityo them will successully complete this process due to crucialcheckpoints or controlling autoreactivity.

-cell unction in CLL patients is impaired and, atthe same time, B-cells produce an insufficient amount oantibodies inducing hypo-gammaglobulinemia [, ].Tese dysunctions are a hallmark o CLL since the onset othe disease. able summarizes some o the immunologicalterations described in CLL patients.

Inections anda higher rate o secondtumors with respectto normal subjects are considered a possible consequenceo such a proound immunosuppression. Moreover, -cellimpairment and abnormal interactions between and B-cellscause a deciency o the immune surveillance system acil-itating the emergence o resting normal B-cell clones, ableto produce autoantibodies against erythrocytes, granulocytes

and platelets [].More recently, regulatory -cells (regs) have been evalu-

ated in CLL []. Tey were ound abnormally expressedin CLL patients and have been considered to be also involvedin the escape o autoreactive clones [, ]. CLL cellsprobably deliver inhibitory signals to regs preventing theelimination o autoreactive and B-cells.

Te source o autoantibodies involved in autoimmunedisorders associated with CLL is stil l an unresolved question.Some investigators demonstrated that autoantibodies are dueto the neoplastic B-cells, while othershavesuggested that theyare produced by resting normal B-cells as a consequence o -cell disturbance[].

Overall, our main mechanisms o autoimmune disease inCLL have been proposed (Figure) and recently reviewed byHodgson etal. []. Firstly, a role o efficient antigen presentingcells or leukemic B-cells has been demonstrated in CLL-associated AIHA by Hall et al. []. In act, they showedthat CLL cells may act as efficient antigen presenting cells

(APCs) inducing a -cell response that, in turn, inducesthe subsequent activation o resting normal B-cells andthe production o polyclonal autoantibodies. CLL cells mayalso act secreting inhibitory cytokines that alter immunetolerance, thus acilitating the escape o sel-reactive clones.Tough rarely, CLL cells may act as effector cells secretinga pathological monoclonal autoantibody. Finally, CLL cellsmay be stimulated through their polyreactive B-cell receptor(BCR) that recognizes auto-antigens.

Production o monoclonal or polyclonal autoantibodiesby B-cells against eryhtroid cells (that may be involvedat any stage o differentiation) and, though more rarely,autoantibodies against erythropoietin receptor or the red-cell signaling pathway, are thought to play a key role in thepathogenesis o CLL associated-PRCA [,]. However, analternative notion supporting the main role o and NK-cells in suppression o erythropoiesis has also been proposed(reviewed by DArena and Cascavilla []). In act, experi-mental studies showed that the inhibition o erythropoiesisis due to the dysunction o the so-called cells carryingthe Fc receptor or IgG (CD) []. Tese cells wereshown to be increased in bone marrow o patients with CLL-associated PRCA and inhibit erythroid growth in vitro [].In addition, these cells are not able to support the growth oburst-orming unit-erythrocyte (BFU-E) as usually happensin normal individuals [].

HLA class I proteins inhibit killer-cell inhibitory recep-tors (KIRs) normally expressed on cells and like NK-cells. Handgretinger et al., analyzing a case o LGL leukemia-associated PRCA, proposed an intriguing model o inhibitiono erythropoiesis in PRCA []. KIRs and HLAclass I antigenligation inhibits lysis o target cells by NK or cells. Teselatter lyse cells in a MHC unrestricted manner, thus targetingcells that do not display HLA class I proteins. Usually, BFU-E express HLA class I antigens and, as the maturation oerythroid cells progress, a down-regulation o such antigensis seen. In this way, a clonal expansion o NK-cells or cells is able to induce pro-erythroblast lysis, determining theclinical picture o PRCA.

4. Fludarabine-Related Autoimmune AIHA

Fludarabine (FAMP) is the most effective and extensivelystudied purine analog in B-cell chronic lymphoid malignan-cies. Te combination o FAMP, cyclophosphamide and anti-CD monoclonal antibody rituximab (FCR regimen) hasemerged as the current standard o care in the treatmento younger CLL patients []. AIHA may complicate FAMPtherapy []. able summarizes data on the incidence oAIHA in FAMP-treated CLL patients rom some o the largeststudies published so ar. As shown, Di Raimondo et al.reported (%) cases o AIHA in a cohort o CLLpatients treated with FAMP alone []. welve (%) out o

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: Reported incidence o AIHA in udarabine containing regimen treated patients with CLL.

Reerence No. o AIHA cases/no. o

patients evaluatedRelative number o

AIHA (%) ype o therapy given

Di Raimondo et al. [] / FAMP alone

Myint et al. [] / FAMP alone

Mauro et al.[] /

/..

FAMP + prednisoneChlorambucil + prednisone

Catovsky and Richards[]///

ChlorambucilFAMP

FC

Borthakur et al.[]

All cases/

DA-positive/

All cases.

DA-positive.

FCR

Hallek et al. [] /

/%

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CLL patients were reported to develop AIHA afer FAMPtreatment by Myint et al. []. In addition, out o patientsre-treated with FAMP afer hemolysis control developed anexacerbation o their AIHA. In a series o , CLL patientsstudied at a single institution or more than years, Mauroet al. ound cases o AIHA (.%) in the group o patients

treated with FAMP and prednisone versus cases (.%)observed in the group o patients who had received chlo-rambucil and prednisone []. Tirty-eighth cases o AIHAoccurred in a French multicenter randomized trial com-paring FAMP alone versus cyclophosphamide, doxorubicinand prednisone (CAP) or cyclophosphamide, doxorubicin,

vincristine and prednisone (CHOP), as rst-line treatmento advanced CLL patients; no statistically signicant differentdistribution in the three arms was observed[]. Catovskyand Richards reviewed data rom MRC CLL trials in the last years []. Te incidence o AIHA was .% in untreatedpatients, while it was % in treated patients, the majority othem receiving alkylating agents. Te same group reportedthe nal results o the LFR CLL multicenter trial in whichpatients with A progressive, B and C Binet stage CLL wererandomized to receive chlorambucil, FAMP alone or FAMPplus cyclophosphamide (FC) []. AIHA was less commonin the FC group than in other groups, thus suggesting aprotective role o cyclophosphamide when combined withFAMP. Te German CLL study group also reported a lowerincidence o AIHA with FC compared to FAMP alone [].

Concerning the use o rituximab, Borthakur et al. per-ormed a retrospective analysis o patients treated atMD Anderson Cancer Center with FCR []. Tey oundthat (.%) o them developed AC on or afer therapy: (.%) patients experienced AIHA and (.%) PRCA. Ointerest, AIHA occurred despite DA negativity in % ocases, as FCR may mask DA positivity below the thresholdo detection o commonly used tests.

Finally, Hallek et al. reported data rom CLL patientsenrolled in a randomized trial comparing FCR to FC; nodifference (% versus

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specic treatment should be applied only when such anapproach has ailed. Conventional immunosuppressive ther-apy is usually used to treat these disorders. Rituximabalone orcombined with other immunosuppressive agents, currentlyappears to be the preerable therapeutic option.

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