Dealing with pre-existing chronic in cancer patients— considerations and consequences in the clinical praxis

Anna-Birgitte Thinggaard1, Gabor Liposits1a and Niels Fristrup1,2

1Department of Oncology, Regional Hospital West Jutland, Denmark 2Department of Oncology, Aarhus University Hospital, Denmark ahttps://orcid.org/0000-0002-8204-3949

Abstract

Chronic neutropenia is a rare but important challenge with substantial clinical implica- tions for patients receiving antineoplastic treatment. Treatment-induced neutropenia is a well-known adverse event during and some targeted treatments. Guide- lines for administering chemotherapy are rather strict to protect the patient from severe and life-threatening complications. Consequently, patients with chronic neutropenia may receive suboptimal antineoplastic treatment. Autoimmune neutropenia or chronic idio- pathic neutropenia (CIN) may affect the antineoplastic treatment by causing delayed drug delivery, dose reductions and early discontinuation of treatment. CIN is characterised by Case Report the onset in late childhood or adulthood, affects mostly women, is clinically benign and has rare spontaneous remission. Here, we elucidate the challenges related to chronic neutropenia when administering chemotherapy through two clinical cases. Guidelines may need to be revised in order to optimise the treatment of patients with asymptomatic chronic neutropenia, thus personalising the medical decisions for each patient.

Keywords: chronic neutropenia, autoimmune neutropenia, chronic idiopathic neutropenia, chemotherapy, targeted therapy, monoclonal antibodies Correspondence to: Niels Fristrup Email: [email protected] ecancer 2020, 14:1131 https://doi.org/10.3332/ecancer.2020.1131 Introduction Published: 29/10/2020 Received: 11/06/2020 Neutropenia is characterised by abnormally low levels of granulocytes (further ) in the blood. The neutrophils play an important role in the immune response Publication costs for this article were supported by ecancer (UK Charity number 1176307). and neutropenia is known to increase the risk of serious [1]. The normal neu- trophil count is defined between 2 and 7 × 109/L, with levels below 1.5 × 109/L defined Copyright: © the authors; licensee as clinically relevant neutropenia [1]. Neutropenia is a well-known adverse event related ecancermedicalscience. This is an Open Access article distributed under the terms of the to chemotherapy and consequently increases the risk of during treatment in Creative Commons Attribution License (http:// patients with cancer. creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and Neutropenia is divided into three categories depending on the severity of the condition: reproduction in any medium, provided the original mild (>1 × 109/L), moderate (0.5–1 × 109/L) and severe neutropenia (<0.5 × 109/L) [2]. work is properly cited.

ecancer 2020, 14:1131; www.ecancer.org; DOI: https://doi.org/10.3332/ecancer.2020.1131 1 neutropeniaas aneutrophilis classified count <1.5 ×10 The prevalence of neutropeniais estimatedin Caucasians beinglessthan1%andchronic neutropenia approximately 0.1%[7,8].Chronic event related to theadministration of CDK4/6iissevere neutropenia [5]. lead to cell cyclearrest (G1-S phase) [5]. Thisleads to inturn senescent-like cellular phenotype inthetumour cells [6]. A common adverse An exampleof non-chemotherapyneutropeniainducing drugs is cyclin-dependent kinase4/6inhibitors (CDK4/6i). These targeted agents will bepostponeduntil thebonemarrow functionrecovers. and thrombocytes, althoughit varies amongtreatment regimens [4].If these requirements are not met, the treatment is contraindicated and priate function. The administration of chemotherapy or other drugs neutropeniainducing requires a certain level of neutrophils ulocyte colony-stimulatingfactor (G-CSF) admission, andmaydelay cause intreatment administration, andresult ineither dosereduction or treatment withdrawal, or additionof gran- Febrile neutropenia isapotential life-threatening adverse event related to systemic antineoplastic treatments (Table 1),leadingto hospital neutropenia’ canbediagnosed[9,10]. If noobviousreason forneutropenia the be found,can a bonemarrow biopsy isusually recommended. Only if alltests are normal,‘idiopathic tropenia, when neutropenia isfirst diagnosedandproven persistent inboth bloodtests. andmultiple time marrow dysfunction or malnutrition/starvation [9]. in all ages and may be insignificant or life-threatening. A range of extrinsic and intrinsic factors may cause chronic neutropenia, e.g., bone ecancer 2020, 14:1131; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1131 Table 1. Anti-cancer drugsleadingto neutropenia. Table 2.Haematological examination of potential conditions/causes of chronic neutropenia. Plant alkaloids Topoisomerase inhibitors Anti-tumour Alkylating agents Antimetabolites Chemotherapy PARP inhibitors Protein kinaseinhibitors Cyclin-dependent kinase4/6inhibitors Monoclonal antibodies Targeted agents Past medicalhistory (ethnicity, frequent hospitalisation asachild,recent infections, etc.) Social details Demographic factors Specific bloodtestto exclude rheumatological or haematological conditions Concomitant symptoms Current symptoms andhistory (includinguseof drugs,malnutrition,comorbidity, recent travels or primary haematological malignancy) Drug type [3]. Prior to chemotherapy administration, new haematological tests are required to ensure appro- Vinorelbine, paclitaxel, docetaxel, etoposide, irinotecan, topotecan Irinotecan, topotecan, etoposide Doxorubicin, epirubicin,mitomycin C Cyclophosphamide, carboplatin, oxaliplatin, cisplatin, lomustine 5-flourouracil, methotrexate, capecitabine,gemcitabine Olaparib, niraparib, rucaparib, veliparib Ibrutinib Palbociclib, ribociclib,abemaciclib Rituximab (CD20), daratumumab (CD38), infliximab (TNF), venetoclax (BCL2) Table thefactors 2summarises or conditions that are acommon causefor selective neu- 9 /L thatpersists for more than3months [9]. The condition spans widely; itoccurs Examples 2

Case Report thrombocytes ≥75×10 ≥100 ×10 For carboplatin in combination with doxorubicin, the haematological treatment requirements are neutrophils ≥1.5 × 10 Carboplatin,doxorubicin and paclitaxel areeffectivemost the among cytotoxic agents usedfor thesystemic treatmentof ovarian cancer [16]. and are especially poor in women +70-year old[15]. Ovarian cancer is the eight mostcommon causeof cancer-related deaths in women ecancer 2020, 14:1131; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1131 treatment requirements are neutrophils ≥1.5×10 cer intheadjuvantsetting (anCapecitabine oral prodrug of 5-fluorouracil) and5-fluorouracil have longbeenthebackboneof chemotherapy for stages II–IIIcolon can- Colorectal cancer (CRC) isthethird mostcommon causeof cancer-related deaths in women [12]. optimal anti-neoplastic treatment. Here, we present two casesof chronic neutropenia incolon cancer (case #1)andovarian cancer (case# 2)andhighlight thedilemmaof sub- primary AIN ismore frequent inchildren andoften self-limiting by theonset inlate childhoodoraffects adulthood, more women thanmen,isclinically benignandhasrare spontaneous remission, whereas Secondary byis caused AIN someother(autoimmune) underlying is not disease.CIN associated with other pathologies.is characterised CIN yet available [1]. AIN ischaracterised by antineutrophil antibodies circulating inthebloodstream. It canbeidiopathic (primary) or secondary. Chronicidiopathic neutropenia (CIN) neutropeniaand autoimmune (AIN)are often interchangeable inadultssince noreliable antibody test is The estimates may vary dependingonthetreatment regimen (dose/m paclitaxel alone. Table 3shows theestimated riskof febrile neutropenia related to doxorubicin/carboplatin, paclitaxel/carboplatin, and capecitabine/5-FU daily (maximum dosage 400 mg × 2) on a continuous basis. Every treatment cycle is 28 days and requires neutrophils ≥1.5 × 10 × ≥1.5 neutrophils requires and days 28 is cycle treatment Every basis. continuous a on 2) × mg 400 dosage (maximum daily platinum-sensitive breastcancer gene (BRCA)-mutated relapsedovarian cancer [20].Olaparib isadministered ascapsulesconsumed twice Ovarian cancer treatment polywith (ADP-ribose) polymerase inhibitors (PARPi), asolaparib,isapproved such asmaintenance therapy in the combination may increase themyelotoxicity of capecitabinethrough theproliferative activity of thebonemarrow [19]. symptoms in caseof persisting neutropeniaor asaprophylaxisfor febrile neutropenia [18].Side effects are rarely severe andmostly consist of flu-like G-CSF stimulates thegenesis of white bloodcells. This isespecially important duringadjuvant treatment inorder to maintain doseintensity During intermediate or high-risktreatments, addedtreatment myeloidwith growth factor or G-CSF may benecessary. As agrowth factor, treatment intention andperformance status Table 3.Risk of febrile neutropenia varies amonganti-cancer drugs. Paclitaxel alone Capecitabine/5-FU Paclitaxel/carboplatin Doxorubicin/carboplatin 9 [9, 18]. Treatment G-CSFwith israrely used patientthe when isbeingtreated with capecitabinesince ithasbeensuggested that /L, andfor weekly paclitaxel neutrophils ≥1.5×10 Regimen 9 /L [21]. /L [13]. The durationof treatmenthas beenproven mostefficient when given for sixmonths [14].Haematological [18]. High (>20%) Low to intermediate (<20%) Low (≤10%) Low (≤10%) 9 /L andthrombocytes ≥100×10 Estimated riskof febrile neutropenia 9 /L andthrombocytes ≥50×10 [9, 11]. 2 , weekly administration (adm) vs three weekly (q3w), age, comorbidity, 9 /L. [12]. Mortality rates and survival depend greatly on age 9 /L. References [17, 18] [17, 18] [17, 18] [17, 18] 9 /L andthrombocytes 9 /L and 3

Case Report ecancer 2020, 14:1131; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1131 Figure 1.Illustration of theneutrophil count since cancer surgery was performed. Hospital West Jutland, inorder to receive adjuvant chemotherapy. roscopicradical surgery, hyperthermic including intraperitoneal chemotherapy. She was referred to theDepartment of Oncology, Regional A 67-year-old woman,diagnosed stageFIGO with IIICBRCA-mutated high-grade serous ovarian adenocarcinoma in2016,underwent mac Case 2 surgery (November 2018)until treatment was terminated (October 2019). Myelodysplasticsyndrome (MDS) was excludedas areason for theneutropenia. Figure shows 1 thelevel of neutropenia from thedate of admitted with febrile neutropenia. The patient was referred to the Department of Haematology in November 2019 for diagnostic work-up. motherapy wasseveral postponed fewer times, treatments were administered andthedose was reduced (Table 4 ). The patient was never The patient was candidate to adjuvant treatment However,capecitabine. with dueto unexplained mildneutropenia, thestartof theche- The woman hadnoconcomitant diseasesandtook nomedication at timeof referral. of Oncology, Regional Hospital West Jutland,for adjuvant chemotherapy after surgical removal of both primary tumour andliver metastasis. A 57-year-old woman, diagnosed left-sidedwith colon cancer in2018and with synchronous liver metastasis, was referred to theDepartment Case 1 Table 4. Treatment overview case#1. Intended treatment Postponements dueto low neutrophil count Final treatment Capecitabine (1,000mg/m 11 timesintotal (each lasting1 week) Capecitabine 1,150mg(75%)day 1–14,6seriesintotal 8 seriesintotal 2 twice daily) 1,500mg(100%)day 1–14q3w, 4 -

Case Report virus-testing was negative.virus-testing was excludedas areason forneutropenia. the The bonemarrow was describedashypoplastic not but dysplastic. Human immunodeficiency In Septemberpatient 2018,the was referred to theDepartment of Haematology andabonemarrow biopsy was MDS carriedout. was treated with corticosteroids daily, andfuture data were therefore nolonger valid. of neutropenia since surgery was performeduntiland up November 2019 when thepatient, dueto adeclineinher general condition, was were accepted.All alongthetreatment course, thepatient reported general well-being andnoepisodeof . Figure 2shows thelevel count dueto hospitaladmittance andtreatment with corticosteroids. ecancer 2020, 14:1131; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1131 *Increase inneutrophil count to 14.92×10 Figure 2.Illustration of theneutrophil count since cancer surgery was performed. count (>1.0×10 gression andpersistentneutropenia.Later treatment inthe course, a weekly paclitaxel regime with reduced requirements to theneutrophil In thepalliative setting,the patient candidate became for olaparibtreatment; it was started, stopped but after only two cycles dueto pro- nificantly reduced despite additionof G-CSF (Table 5 ). Dueto chronicmoderate neutropeniaeven before chemotherapy initiation, treatment was postponedseveral andthedose times was sig- The patient hadnoconcomitant diseasesexcept for allergy-induced asthmathat required nodaily medication. * At thistime,only Olaparib capsules were available Table 5. Treatment overview #2. Postponements dueto low neutrophil count Administered treatment Planned treatment after relapse Intended treatment 9 /L) was administered,treatments but were further postponedanddose-reduced several timesdespite lower neutrophils 9 /L dueto onetreatment with G-CSF (Longuex 6mg)–nochemotherapy was given. **Increase inneutrophil 16 timesintotal (each lasting1 week) Paclitaxel 77mg(60%) weekly administered Olaparib terminated after only two series.Hereafter: total, andthentreatment with Olaparib 400mg×2(100%)q4w* Carboplatin 609mg(AUC 5)+G-CSF (Longuex 6mg)q3w, 3–6seriesin in total Paclitaxel 287mg(100%)andcarboplatin 640mg(AUC 5)q3w, sixseries 5

Case Report plausible explanation was found. Treatment hassince beenterminated dueto thedeclineof thepatient’s general condition (January 2020). The Department of Pharmacology was contacted inNovember 2019to investigate whether theneutropenia could bedrug-induced, no but ecancer 2020, 14:1131; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1131 of cancer patients chronicwith neutropenia. Furthermore, when patients present with unexplained neutropenia before cancer treatment In conclusion, doseintensityfor iscrucial many antineoplastictreatments, and current guidelines leave noroom for personalised treatment Conclusion ‘fractionalthe kill’ and‘log cell kill’ hypothesis Ifintervals the are prolongedto due neutropenia,therethen isariskof lesseffective chemotherapy. This phenomenonisdemonstrated in assumed beingsuboptimal. Optimaltreatment chemotherapywith relies entirely onintervals anddose.If doseintensity iscompromised, thentreatment efficacy is Discussion such astheseto avoid insufficient antineoplastic treatment. restrictionssame as other patientsor whether it wouldbe appropriate for an individualclinicaljudgment to deviate from regulations incases Thethat question remains is whether asymptomaticpatients unexplainedwith neutropenia (due toor CIN be treatedAIN) should under the patients within the framework of thecurrent guidelines. is not toconditionunderlying diagnose the thatthe neutropenia caused inthefirst place, to but illustrate thecomplexity of dealing with such CIN/AINexplanationplausible isthemost to the neutropenia describedintheabove-mentioned cases. The objective of however, thisarticle, ment combination of chemotherapy andmethotrexate canalsobean issue. treatments are usually only recommended when thepatient have symptoms dueto theneutropenia, which was not thecasehere. The treat- cause. Treatment could consist of immunoglobulin or methotrexate dependingontheunderlyingreason for the condition. However, these Different suggestions in terms of treatment of the neutropenia can be speculated requiresbut thorough investigation regardwith to the treatment dueto a reduction inthedestructionandaglucocorticoid-induced demargination, which isconsistent case#2(Figurewith 2). However, AIN cannot beexcluded here since none of thecases was tested for autoimmune antibodies. In AIN, neutrophils riseafter steroid excluded,CIN or AIN seemsmore likely. CINseemsto match both casesinterms of age frequency, gender andchronic distribution tendency. Since thecondition inboth casespresentedclinical here hadbeenpresent for more than3months andother apparent reasons hadbeen over time. neutropenia wouldevery happen 2–5 weeks [23]. This isnotcase forthe thetwo patients here, asthelevel of neutropenia hasnot changed Cyclicneutropenia isaparticularly rare condition in the neutrophilwhich count fluctuates between abnormalandnormal values. Episodes of Conditions such ascyclic neutropenia, AIN andCINare rareto anddifficult diagnose[23]. chemotherapy (and other drugs), infections, metabolic disorders or vitamin deficiencies amongother factors cancauseneutropenia [9]. No particular reason for neutropenia was explained inthetwo clinicalcasesandmany conditions may leadto chronic neutropenia.Cancer, markedly delayed initiation of treatment dueto neutropenia when they were first referred to theDepartment of Oncology. to maintain doseintensity dueto unexplained neutropenia, possibly resulting inlesseffective treatment. Furthermore, both patients hada The other cell lines remained normal. These patients may have had asymptomatic neutropenia for years. In both cases,it was not possible In both cases presented here, the neutropenia was present even before chemotherapy was initiated and gave neither patient any symptoms. Thetherefore guidelines donottake patient individual characteristics into consideration andleave noroom for individualmedicalassessment. Chemotherapyclearly guidelines state thatno person be treated should with chemotherapy if theneutrophils are below apredefined level. ments anddosereductions are implemented dueto neutropenia. ficientantineoplastic treatment is higher. In line this, with we believe that thetreatment with non-cytotoxic drugsissub-optimal if postpone- [22]. Likewise,if neutropenia results inalower dosage of chemotherapy, thentheriskof insuf 6 -

Case Report 12. 11. 10. ecancer 2020, 14:1131; www.ecancer.org; DOI:https://doi.org/10.3332/ecancer.2020.1131 References The authors received nofinancialsupportfor theresearch, authorship, and/or publication of thisarticle. Funding has any financialor otherwise competing interests that could create any conflict of interests. Beyond this,authors declare thatorsupport no financial other benefits from commercial sources have beenreceived andnoneof theauthors GL: No relevant COIs Niels Fristrup MDPhD, Advisory Board Member, Pfizer inc. Disclosures We stillknow littleabouthow to treat chronic neutropenia incancer patients, and whether itshouldbetreated at all. initiation, ahaematological examinationquickly shouldbecarriedout to avoid unnecessary postponement of thecancer treatment initiation.

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Case Report