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Home , Hereditary angioedema

A patient with chronic lymphocytic leukemia and acquired : correlation of clinical and biochemical response to CLL therapy

GR Mohyuddin and I Rabinowitz

University of New Mexico Cancer Center, 1201 Camino de Salud NE, Albuquerque, NM 87131, USA

Correspondence to: GR Mohyuddin. Email: [email protected]

Abstract

Acquired angioedema (AAE) is a result of an acquired deficiency or inactivity of the C1 esterase inhibitor (C1-INH). There is a well-known link between AAE and lymphoplasmacytic disorders. A 65-year-old woman who was diagnosed with chronic lymphocytic leukemia (CLL), presented with recurrent episodes of angioedema. Although no association between the CLL and angioedema was initially recognized, further workup showed her to have low C1-INH levels. Chemotherapy helped prevent subsequent episodes, but three years later she redeveloped angioedema. She was then placed on ofatu- mumab maintenance and has since remained free of angioedema. Knowledge of this rare disease and anticipation of the link between CLL and AAE can prevent further attacks and associated morbidity. Case Report

Published: 14/02/2013 Received: 22/11/2012 ecancer 2013, 7:292 DOI: 10.3332/ecancer.2013.292

Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1 free fromanyrecurrencesofangioedemaforoverayear follow-up. 2011, receiving seven weekly doses and then on a monthly schedule for another four doses. As of January 2013, the patient has remained patient previously was allergic to rituximab, we decided to try ofatumumab. The patient was treated with ofatumumab beginning November thereafter.years three for angioedema the of As episodes chemotherapy,no after had normalize she to clinically failed levels C1-INH her plasma and diphenhydramine. Her C1-INH function in December 2011 was 25%. In reviewing the patient’s history, we noted that although Within two months in October 2011, she had another recurrence of angioedema, which again was treated with , fresh frozen lymphocytosis andsplenomegalyhadresolvedremainednormal. At that time we did not offer her any further treatment for her CLL, which showed no evidence of relapse on blood tests and CT scans. Her hydramine. HerlastC1esterasefunctionwas12%inMay2011. a repeat episode of angioedema. She was not intubated this time; however, she received corticosteroids, and diphen until stable remained patient Our angioedema. her for treatment further no received thus patient Our refused. 2011,August had she when func- mg/dL12 respectively.were 55%, and tion and rheumatology,to she referred but was She hydroxycholoroquine, with offeredtherapy who her level esterase C1 her chemotherapy, of end the At 2008. October in (CVP) prednisone and vincristine cyclophosphamide, of cycles six completed She regimen. the from discontinued subsequently was it and cycle second the during rituximab to reaction severe a after completion of six cycles of rituximab, cyclophosphamide, vincristine and levels prednisone (R-CVP). Her esterase chemotherapy was C1 complicated by the repeat chemotherapy,and initiate to decided we CLL, and angioedema acquired between association the Given she receivedafterhersecondepisode. that steroids of course tapering a to due been have part in may which 53%, to risen had activity later,esterase month C1 one her studies binding assay and complement 3 levels were normal, but complement 4 levels were noticeably low. Interestingly, when we repeated these (reference mg/dL 4 was level esterase value, >11C1 mg/dL) her and her C1 episode, esterase activity second was 5% (reference her range, 68%–200%). During Her rheumatoid factor done. was elevated was at 87. Her angioedema C1Q her evaluate to workup complete a In April 2008, she again developed an attack of angioedema, necessitating another intubation and hospitalization for a few days. This time finally, acompleteinabilitytobreathe. There werenoincitingepisodesthatthepatientcouldpointtocausedthisoccur. and mouth her of swelling sting, bee a to similar mouth and her around tingling a as beginning episodes the described patient The of atopyorangioedema. history previous no had She hydrochlorothiazide. and D, vitamin calcium, included time that at taking regularly was she The hypertension. and osteoarthritis included co-morbidities Her asymptomatic. therapy,was on she started as been not had She phocytosis. and hospitalization in the ICU for two weeks. She had been diagnosed with CLL in July 2007, after intubation presenting with splenomegaly and lym- required that angioedema, of event acute an after clinic, oncology our to presented woman 65-year-old a 2007, November In Case description tions mayresultintreatmentsthathelppreventcomplicationsandrecurrences,asourcasehighlights. clinical manifestationsofangioedema,suchaslaryngealedema,skinandabdominalpain[ the causes ensues that activity and complement excess The of C1-INH. or inactivity deficiency of an acquired is a AAE result Introduction There is a well known link between AAE and lymphoplasmacytic disorders lymphoplasmacytic between and AAE link known well a is There

2 [1, . Recognition and understanding of the disease associa disease the of understanding and Recognition 3]. 1, 2 ] . ecancer www.ecancer.org 2013,7:292 - -

Case Report it iscertainlypossiblethatotheraspectsoftheimmunesystemarenottestedbyourassaysplayaroleinrecurrent attacks. pendent of its effect on the tumor. A part of that immunosuppression is reflected in the rise of the C1 esterase functional assay level, but inde- attacks, angioedema further prevent to state sufficientimmunosuppressive a produce CLL, for used treatments the that be could It status. disease CLL her with correlated be to seem not does angioedema the Thus lymphocytosis. or splenomegaly of recurrence no with in 2008 chemotherapy first her since CLL Her in remission was correlated. strongly very it is not events, angioedema her and assay she had no episode of angioedema (20% in August 2009). Although there seems andC1 to low was be C1-INH her patients a the relationship when when 2011times between were However,the there December). late C1 in 25% esterase in and May functional in and (12% again low (5%) also was esterase low was esterase C1 her when 2008 early in angioedema of episodes had patient The attacks. in noted As increases that agent an , or drugs antifibrinolytic C1-INH synthesisandhasbeenshowntobeefficacious [12]. using or condition, underlying the addressing involves treatment Long-term plete resolutionwithasinglesubcutaneousinjection[ to have success in treating acute attacks of acquired angioedema. Eight patients were studied, and of a total of 48 attacks, 47 achieved com- Icatiban is a bradykinin B2 receptor antagonist, which is an established therapy for hereditary angioedema. In a recenttreatment ofacuteattacks.Incaseswherethesearenotavailablesuchasinourpatient,freshfrozenplasmacanbe given study, it was also shown Drug and Food P,The Berinert concentrate, C1-INH the approved has Administration Kalbitor,, inhibitor a and the for ing 32patientswith AAE, Castellidiscoveredthat13(40%)hadMGUSand nine (28%)hadlymphoproliferativedisease 7–9]. However, there exists abundant literature on the association of AAE with lymphoplasmacytic disorder of different types. While review angioedema with associated lymphoma lymphocytic small CLLand of cases previous 17 were there knowledge, our Toof best the the gastrointestinaltractandtongue. AAE typicallypresentsinthefourthdecadeoflife,orlater, incontrasttothehereditaryform[6]. Due to low levels of C1-INH, C1Q and C4, angioedema symptoms keep recurring and presenting with to the upper respiratory tract, Abnormalities in this condition include an increased consumption of C1-INH and excessive activation of the classical complement pathway. picture andabsenceofothercausativefactors,canleadonetoadiagnosis clinical classic a to addition in features, aforementioned The with AAE. patients of 70% to up in shown be can C1-INH to levels. C3 low and activity,levels C1-INH C4 low low include very features diagnostic its exists, diagnosis for criteria uniform no Although of C1-INH[5]. both low levels and function of C1-INH in the circulation and the Type II form is associated with normal levels of C1-INH, but a low function entity,rare extremely an itself in reported is cases AAE 150 around with as angioedemaisrare[ such autoimmunity nonhaematological whereas common, less although seen be also can neutropenia autoimmune and aplasia, cell red pure Autoimmune complications can be seen in 25% of CLL patients. Most common is autoimmune haemolytic anaemia. Immune thrombocytopenia,Discussion Figure 1 , there seems to be a relationship between treatment of the underlying CLL and the frequency of angioedema of frequency the and CLL underlying the of treatment between relationship a be to seems there , 4 ] . 1 1 ] . 3 . It is broadly classified in two types: two Typein classified broadly is by It characterized [3]. is I [1]. ecancer www.ecancer.org [3]. [10]. 2013,7:292 , 4, [3, -

Case Report References The authorshavenoconflictsofinteresttodeclare. Conflicts ofInterest of theseandothervariables. lymphoproliferative disease status, the quantitative C1 esterase functional assay, some other factors that were not tested, or a combination displays the complexity of this association. After careful review of the data, it is unclear whether the angioedema attacks are related to the also patient the However, AAE. and disorders lymphoproliferative between association the of example another yet presents patient The Conclusion and theoccurrenceofangioedemaattacks. level the between correlation partial a shows assay functional inhibitor esterase C1 The attacks. angioedema without time cant signifi patient the afforded CLL. has of Anti-CLLtherapy treatment to correlated angioedema of episodes of Timeline 1: Figure

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