Acute and Long-term Toxicity of Cyclophosphamide

Transplantationsmedizin M. Haubitz: Acute and Long-term Toxicity of Cyclophosphamide2007, 19. Jahrg., S. 26

M. Haubitz

Department of Nephrology, MedicalSchool Hannover

Haubitz M (2007) Acute and Long-termToxicity of Cyclophosphamide. Tx Med19: 26-31

Acute and Long-term Toxicity of Cyclophosphamide

Cyclophosphamid has been widely used in patients with kidneydiseases such as vasculitis, SLE, steroid-resistant nephrotic syn-drome and also progressive IgA-nephropathy. Beside acute side ef-fects like bone-marrow toxicity, infections, haemorrhagic cystitis,gastrointestinal side effects and hair loss, the main concern is thelong-term effect of the drug which may occur years after treatmentwhen patients with end-stage renal disease have received a trans-plant. Incidences increase for tumours, especially bladder carcino-ma, lymphomas and tumours of the skin, for the myelodysülasticsyndrome and the permanent infertility.As most of the side effects are associated with the total dose of CP,dose reduction by stage-adapted treatment, i.v. administration,shorter treatment time and prevention of relapses is an important is-sue. In addition, some side effects may be reduced or even prevent-ed, e.g. bladder toxicity by the use of Mesna, skin tumours by sunblockers, permanent infertility by sperm conservation or by go-nadotropin-releasing hormone analogue. In patients with high CPexposure awareness of the increased tumour risk may lead to earlydetection and the chance or curative treatment.

Key words:cyclophosphamide, toxicity, opportunistic infection, risk of tu-mours, infertility, MDS

Akute Nebenwirkung und Langzeittoxizität vonCyclophosphamid

Cyclophosphamid wird in der Nephrologei bei einer Vielzahl vonErkrankungen eingestzt. So spielt es bei der Therapie der SLE undder systemischen Vaskulitiden eine entscheidende Rolle. Auchbeispielsweise das steroidresistente nephrotische Syndrom undmöglicherweise auch die rasch progrediente IgA-Nephropathiestellen eine Indikation dar.Neben den während der Therapie zu beobachtenden Nebenwirkun-gen, wie der Knochenmarkstoxizität, der vermehrten Anfälligkeitfür Infekte, der hämorrhagischen Zystitis, den gastrointestinalenNebenwirkungen und dem Haarausfall, spielt vor allem dieLangzeittoxizität eine wichtige Rolle. Die Auswirkungen kommenoft erst nach Jahren zum Tragen, wenn der Patient beispielsweisebereits nierentransplantiert ist. Hier ist neben der Erhöhung desTumorrisikos (vor allem für Blasenkarzinom, Hauttumore undLymphome) die Entwicklung eines myelodysplastischen Syndromsund bei jungen Patienten die Infertilität zu nennen.

M. Haubitz: Acute and Long-term Toxicity of Cyclophosphamide Transplantationsmedizin2007, 19. Jahrg., S. 27

Da die meisten Nebenwirkungen dosisabhängig auftreten, kommtder Reduktion der Cyclophosphamidgesamtdosis eine entschei-dende Bedeutung zu. Neben einer engen Indikationsstellung fürCyclophosphamid (z.B. stadienadaptierte Therapie bei granulo-matöser ANCA-assoziierter Vaskulitis) und der i.v. Gabe zur Do-sisreduktion, spielt die verkürzte Therapiedauer mit Cyclophos-phamid und eine remissionserhaltende Therapie zur Vermeidungeiner Retherapie eine wichtige Rolle. Darüber hinaus sind einigeNebenwirkungen vermeidbar oder in ihrer Inzidenz zu reduzieren,wie zum Beispiel die Blasentoxizität durch die Applikation vonMesna, das Risiko von Hauttumoren durch Sonnenschutz oder dieInfertilität durch eine Spermienkonservierung bzw. möglicherweisedurch die Gabe eines Gonadotropin-Releasing-Hormon-Analogon.So sollte schon vor der Gabe von Cyclophosphamid alles getanwerden, um Spätkomplikationen zu vermeiden. Bei Patienten mithoher Cyclophosphamiddosis können Vorsorgeuntersuchungen wieregelmäßige Hautinspektionen und Blasenspiegelungen zu einerfrühen Tumorerkennung mit der Chance einer kurativen Therapieführen.

Schlüsselwörter:Cyclosphosphamid, Toxizität, opportunistische Infektion, Tumor-risiko, Infertilität, MDS

IgA-nephropathy and others [7-10]. Initially the major concerns were the se-vere side effects of the drug duringtreatment, mainly bone marrow toxicityand severe infections, but in the lastdecade long-term toxicity has gainedmore and more attention. Serious life-threatening side effects may occur afteryears when the patient has developedend-stage renal disease and is on dialy-sis or has received a renal transplant. Inthe following I will summarize theacute and chronic side effects of CP,and then concentrate on the preventionand early detection of its toxicity.

Acute Toxicity

The side effects of CP are well knownin patients receiving the drug for thetreatment of solid tumours, lymphomas,leukaemias or for conditioning beforestem cell or bone marrow transplanta-tion. Bone marrow toxicity with oppor-tunistic infections, haemorrhagic cysti-tis, temporary infertility, nausea, vomit-ing and hair loss are seen frequentlywhereas pneumonitis, liver or cardiactoxicity are rare. Patients treated forvasculitis, proliferative lupus nephritisor other renal diseases had a compara-ble spectrum of side effects but withclearly lower incidence and severitydue to the lower dose. The main con-cern in these patient groups is the oc-currence of severe infections with a sig-nificantly rising incidence with increas-ing age of the patients. A patient with anANCA-associated vasculitis aged 65years has a 50 % chance of developinga severe infection, defined by admis-sion to the hospital and intravenousdrug administration. The risk further in-creases to about 70 % at the age of 70years. The spectrum of infections iswide, including not only bacterial infec-tions like pneumonia, endocarditis,spondylodiscitis and Staphylococcusaureus sepsis with a catheter as origin,but also viral and fungal infections.Thus, beside the use of cotrimoxazol toprevent Pneumocystis jiroveci pneumo-nia, recommendations for prophylaxisare hard to give. Although the entire urinary tract is atrisk of toxicity from the metabolite ofCP, acrolein, the bladder is most sus-ceptible because of its prolonged expo-sure. Nevertheless, haemorrhagic cysti-tis is relatively rare in our nephrologicpatient group even if sodium 2-mercap-toethane sulphonate (mesna), a sub-stance that inactivates acrolein, is notused. This is mainly due to fluid admin-istration in patients with intravenous CP

Cyclophosphamide was first synthe-sized in 1958 by Arnold, Bourseaux andBrock (Figure 1). It is an alkylatingagent with an active metabolite leadingto DNA cross-linking. In patients withautoimmune and kidney diseases thecareer of this drug began when Faucidecided to use it in patients with We-gener´s granulomatosis. Before his reg-imen, still known as the “Fauci proto-col”, patients were treated with steroidsalone and had a median survival of 12.5months [1]. Adding azathioprine orchlorambucil had only a marginal im-pact on mortality but the treatment withoral CP together with steroids gavemore than 90 % of the patients thechance of long-term survival [2]. Sincethen CP has been used for many renaldiseases and is still given to most pa-tients with proliferative lupus nephritis[3,4] and ANCA-associated systemicvasculitis [5,6], Goodpasture syndromeand patients with other systemic vas-culitides [7]. In addition, CP is adminis-trated to patients with steroid resistantnephrotic syndrome due to minimalchange nephropathy or focal segmentalglomerulosclerosis, to patients withmembranous nephropathy, progressive Fig. 1: Chemical structure of cyclophosphamide


treatment and to a relatively low dailydose in orally treated patients. Othergroups have reported an incidence of 12% or even 29 % in patients with Wegen-er´s granulomatosis [11,12]. As seriousallergic reactions to mesna are rarelyseen [13], the benefit clearly outweighsthe risk in these patient groups too.However, the relation of CP-inducedcystitis and the development of bladdercancer have not been defined and up tonow there are no data showing that therisk of a bladder carcinoma can be re-duced by the use of mesna.

Chronic Toxicity

The main concerns regarding CP ad-ministration are the increased risk of tu-mours, of the myelodysplastic syn-drome (MDS) and gonadal toxicity. Cyclophosphamide has been shown toincrease the incidence of malignanciese.g. of the bladder, the haematopoeticsystem and the skin. There is a 1.6- to2.4-fold overall increase in malignan-cies [14,15], depending on the total CPdose and the time of follow-up. For skincancer the risk increases up to 10.4-fold[14], for lymphomas up to 11-fold [15]and for leukaemia up to 5.7-fold [16].Regarding bladder carcinoma, the inci-dence varies between less than 1 %[11], 3 % [14,15] and 5 % [12] corre-sponding to a 5- to 33-fold increase.The risk rises with the total CP dose ad-ministered and the follow-up, and an in-cidence of 16 % has been reported after15 years [12]. It is difficult to pinpoint acritical dose. The data of Baker et al. inpatients with rheumatoid arthritisshowed increasing numbers of malig-nancies, especially of the bladder, in agroup of patients with more than 70 gCP and a follow-up time of more than 8years [17]. Episodes of non-glomerularmicrohaematuria are a risk factor forthe development of bladder cancer [12]and occur more often in smokers. How-ever, microhaematuria is not a reliablemarker as these episodes were not al-ways frequent and recurrent. Cytologicurine examination is of limited useful-ness in monitoring patients at risk as itis relatively insensitive for the detectionof low-grade bladder cancer [12]. Regarding the MDS, the incidencevaries between 2 and 8 % [11,12].Myelodysplastic syndrome occurs latein the course of the disease (median 60months after diagnosis) after a median

CP dose of 112 g [11]. It may evolve toan acute leukaemia even after a shorttime. For most of the patients, the prog-nosis is bad and the median survival isonly 6 to 12 months. A dose-dependent destruction of germi-nal tissue by CP leading to temporary orpermanent infertility has been shown.The most common findings in men areazoospermia and abnormal serum go-nadotropin levels, due to the loss of thegerminal epithelium lining the seminif-erous tubules and Leydig´s cell dys-function (see also Figure 3a). In womenCP-induced ovarian toxicity is heraldedby the onset of irregular or infrequentperiods and may progress to amenor-rhea, permanent infertility and prema-ture ovarian failure with elevated levelsof gonadotropins and decreased levelsof estradiol leading to physical andemotional consequences. Despite manypublications, no data allowing reliableprediction of gonadal toxicity are avail-able. Chapman concluded that by thetime 18 g CP has been applied orally, allmen will have developed azoospermia.The chance of regeneration decreaseswith an increasing total dose but an up-per limit cannot be given [18]. Inwomen, permanent infertility arises inmost of them after total doses greaterthan 25 g. However, the incidence ofovarian failure depends on age and old-er women are more likely to progress topremature ovarian failure after therapybecause they have a smaller number ofoocytes at initiation. In patients with lu-pus nephritis, CP therapy resulted inovarian failure in all women older than

30 years, in approximately 50 % ofthose aged 20 to 30 years and in 13 %of patients younger than 20 years [19].Recently Manger et al. have describedcomparable results [20].

Prevention of Toxicity

The main strategy for reducing CP tox-icity is still the reduction of the totaldose given to a patient. Stage-adaptedtreatment in ANCA-associated vasculi-tis can avoid CP therapy. It has beenshown that, in a localized or early sys-temic manifestation of the disease withnormal or only slightly impaired renalfunction, remission can be achieved us-ing weekly methotrexate (MTX) in anequivalent number of the patients [21].Remission was delayed among patientswith more extensive disease or pul-monary involvement. The longer timeto remission may be overcome by high-er initial MTX doses and parenteral in-stead of oral administration of MTX.Regarding patients with renal involve-ment or with alveolitis or other severemanifestations, oral CP can be replacedsafely by intravenous pulse administra-tion, leading not only to a reduction ofabout 60 % in total dose but also to amarked risk reduction concerningleukopenia and infections [5]. Theprobability of a toxic event-free period(no death, severe infection, leukopeniaor thrombocytopenia) is more than dou-ble in patients treated with i.v. pulse CPcompared to those receiving daily oraltreatment (Figure 2).

Fig. 2: Probability of a toxic event-free period (no death, severe infection, leukope-nia or thrombocytopenia) in patients with ANCA-associated vasculitis receiving dai-ly oral or i.v. pulse administration of CP


Other important issues are the shorten-ing of treatment time and the avoidanceof relapses. It could be shown that ex-posure to CP in patients with systemic,but not life-threatening, ANCA-associ-ated vasculitis with a creatinine of lessthan 500 µmol/L could be reduced safe-ly by the substitution of azathioprine atremission [6]. Prolonged treatment withdrugs with long-term tolerability likeazathioprine, mycophenolate mofetil(MMF) or MTX reduces the risk of re-lapses. However, up to now no date areavailable regarding the optimal durationof treatment.In patients with lupus nephritis and acreatinine clearance of more than 30-40ml/min, recent data of randomizedstudies suggest that MMF given in adaily dose of 2 to 3 g is at least as effec-tive as and safer than CP treatment[22,23]. The results for 72 months´ fol-low-up suggest that i.v. CP pulses fol-lowed by MMF, or even azathioprine,are more efficacious and safer than

long-term therapy with i.v. CP (NIHregimen) [24]. However, studies onMMF in lupus nephritis are limited by asmall number of patients or a short fol-low-up. In an ongoing Aspreva LupusManagement Study (ALMS) 358 pa-tients with proliferative lupus nephritisare randomized to receive, in additionto prednisolone, MMF or i.v. CP. If thepatients respond to treatment, they arethen randomized again after 24 weeksto receive MMF or azathioprine. As re-cruitment is finished, the first resultsshould be available at the end of theyear. Regarding gonadal toxicity, dose reduc-tion is also an important issue. In ourstudy [25] comparing daily oral to i.v.pulse administration in men, by meas-uring FSH plasma levels, as well as inLewis rats, by investigation testis his-tology and number of foetuses aftermating with healthy female rats, pulseadministration led to a significantly re-duced gonadal toxicity probably due to

the reduction in total dose (Figure 3a, b,4). Recently, administration of a go-nadotropin-releasing hormone analoguein women with severe SLE was associ-ated with a significant reduction in pre-mature ovarian failure [26]. Treatmentwith an gonadotropin-releasing hor-mone analogue should be initiated 1 to2 weeks before the initiation of CP be-cause, during this period, the stimulatedgonadal tissue may be rendered moresusceptible to the toxic effects [27]. Inaddition, the potential risk of precipitat-ing a disease flare with hormonal stim-ulation has to be taken into account inpatients with SLE. More informationregarding this risk will be availablewhen the results of the prospective ran-domized study on protection against go-nadal toxicity in patients with SLE(PREGO study) have been evaluated[20]. Cryopreservation of fertilisedoocytes has been thought to be a possi-bility for female patients who have al-ready selected a partner. Oocyte cryo-

Fig. 3a: Testis histology of a Lewis rat after 6 weeks of pulse CP (A) or daily oral CP (B). A: normal testis histology B: Multifo-cal hypospermatogenesis of moderate degree

0

10

20

30

40

50

60

70

Offspring Leukocytes

Controls

pulse CP

daily CP

[n] [x100/µl]

** p<0.01

***

* p<0.05

Fig. 3b: Leukocyte counts and number of off-springof 10 male Lewis rats in each group (pulse or dai-ly oral CP) mated with two female rats


preservation remains difficult becausethe freeze-thaw techniques used appearto inhibit survival and fertilizability.The cryopreservation of ovarian tissuemight become a possibility in the future[27]. Preventing testicular dysfunction afterCP treatment is still an important issue.The most common strategies includesperm cryopreservation and the use oftestosterone to shut down testicularfunction [28]. Cryostorage of semenhas become a standard practice andshould be offered routinely to men un-dergoing gonadotoxic treatment. The shorter treatment time and a betterprevention of relapses together withother non-CP containing treatment reg-imens and possibly the use of mesnawill probably reduce the incidence ofbladder cancer in the future. However,up to now there have been no datashowing that mesna reduces the risk ofa bladder carcinoma. Regarding the ear-ly detection, non-glomerular micro-haematuria is a risk factor but not al-ways a reliable marker as theseepisodes were transient and sometimesrare. Cytologic urine examination is oflimited usefulness in monitoring pa-tients at risk as it is relatively insensi-tive for the detection of low-grade blad-der cancer [12]. Therefore, in patients with high totalCP doses (> 40-50g) a cystoscopy every1 or 2 years is recommended, evendecades after CP administration.Promising results using a proteomic ap-proach identifying marker proteins for

bladder carcinoma in the urine of pa-tients who have not been immune com-promised have been published recently[29]. Urinary screening using pro-teomics may reduce frequency of cys-toscopy in the future. A regular investigation every 6th to 12th

month is necessary for the early detec-tion of skin cancer. For prevention, allpatients should reduce their sun expo-sure and apply a sun blocker, the use ofwhich should be recommended for allimmunosuppressive regimens.To summarize the awareness that isnecessary with patients who have beentreated with CP, even years ago, I wouldlike to mention the case of a patient ofour outpatient unit. A 65-year-old manwith primary diagnosis of granuloma-tous ANCA-associated vasculitis in1980 had received CP, first orally andlater intravenously, with a total dose ofmore than 100 g. The patient developedend-stage renal disease and received acadaver kidney transplant in 1991.Function has been excellent up to nowwith a creatinine below 150 µmol. Theimmunosuppressive regimen consistsof cyclosporin A and prednisolone. In2000 and 2005 the patient developed re-lapses involving his upper and lowerrespiratory tract and eyes together withmyalgia, arthralgia and general symp-toms. Remission could be achievedwith i.v. CP pulses followed by azathio-prine. Considering his history of CPtreatment and a relapsing course of thedisease, what would you suggest for thepatient? We recommend urinary exami-

nation for microhaematuria every thirdmonth and an annual cystoscopy. Wehave changed azathioprine to MMF toreduce the risk of skin cancer and rec-ommend a regular skin inspection by adermatologist every 6th month and therigorous use of sun blocker. A differen-tial blood count should be carried outregularly. However, MDS cannot beavoided and it is not clear if early detec-tion really improves the prognosis. Finally, it is important to stress thatthere is hardly another drug with suchwell known long-term effects. Newertherapeutic regimens gradually replac-ing CP have proved to reduce toxicity inthe short term but there are no data onthe long-term effects. We will also haveto watch patients carefully followingthese new treatment regimens.

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FSH plasma levels Total CP dose

IU/I

months

** p<0.01

**

** **

0

10

20

30

40

50

0 3 6 3 6

daily oral treatment

i.v. pulse treatment

Fig. 4: FSH plasma levels and total cyclophosphamide dose after oral (n=10) andi.v. cyclophosphamide therapy (n=12) in male patients (normal range <7IU/l in men<= 40 and <14 IU/ml in men > 40 years)


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26. Somers EC, Marder W, Christman GM, Ognen-ovski V, McCune WJ (2005) Use of a go-nadotropin-releasing hormone analog for protec-tion against premature ovarian failure during cy-clophosphamide therapy in women with severe lu-pus. Arthritis Rheum 52: 2761-2767

27. Pendse S, Ginsburg E, Singh AK (2004) Strategiesfor preservation of ovarian and testicular functionafter immunosuppression. Am J Kidney Dis 43:772-781

28. Masala A, Faedda R, Alagna S, Satta A, ChiarelliG, Rovasio PP et al. (1997) Use of testosterone toprevent cyclophosphamide-induced azoospermia.Ann Intern Med 126: 292-295

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Prof. Dr. Marion HaubitzDepartment of NephrologyMedical School Hannover

Carl-Neuberg-Str. 130625 Hannover

[email protected]

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Acute and Long-term Toxicity of Cyclophosphamide