Case Report

J Oncol Pharm Practice

2015, Vol. 21(5) 388–392

Fatal Stevens–Johnson syndrome/toxic ! The Author(s) 2014

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epidermal necrolysis induced by DOI: 10.1177/1078155214533368
opp.sagepub.com
allopurinol–rituximab–bendamustine
therapy

Michael J Fallon1 and Jessica N Heck2

Abstract
Stevens–Johnson syndrome/toxic epidermal necrolysis overlap is an acute hypersensitivity reaction that compromises the
integrity of mucous membranes and cutaneous tissue. While the pathophysiology of this syndrome has not been fully
elucidated, it is commonly associated with the medication use and carries a significant mortality risk of approximately 30%.
No commonalities among causative medications have been identified, and determining the offending agent can be challenging.
This case report describes fatal Stevens–Johnson syndrome/toxic epidermal necrolysis overlap in a patient after receiving his
first cycle of allopurinol, rituximab, and bendamustine treatment for non-Hodgkin’s B-cell lymphoma. An analysis of FDA
Medwatch adverse reaction case reports involving allopurinol, rituximab, and bendamustine is also presented.

Keywords
Rituximab, bendamustine, allopurinol, Steven’s–Johnson syndrome, toxic epidermal necrolysis, tumor lysis syndrome

Introduction B-cell lymphoma with bone marrow involvement. The

Stevens–Johnson syndrome (SJS), Stevens-Johnson patient received allopurinol at a dose of 300 mg by
syndrome/toxic epidermal necrolysis overlap (SJS/ mouth daily to be taken until directed to discontinue
TEN), and toxic epidermal necrolysis (TEN) are a spec- as tumor lysis prophylaxis starting prior to his first
trum of acute hypersensitivity reactions based on body cycle of rituximab and bendamustine (Table 1).
surface area skin detachment of <10%, 10–30%, and Appropriate monitoring parameters including white
>30%, respectively. Compromised mucocutaneous tis- blood cell count, absolute neutrophil count, platelet
sues with extensive tissue sloughing and separation of count, and kidney function were assessed, and all
the first epidermal layer are defining characteristics. were within normal limits with respect to treatment
Numerous medications with diverse indications have parameters prior to initiating chemotherapy.
been reported as the potential causes of these life-threa- Fourteen days after starting chemotherapy, the
tening and potentially fatal skin reactions, yet no com- patient presented to his local hospital with a 3-day his-
monalities have been identified that predict the risk of tory of sore throat, extreme fatigue and weakness,
reaction.1,2 Allopurinol, bendamustine, and rituximab severe pain throughout his skin that was aggravated
have all been demonstrated to cause variable skin toxi- by even slight touch, and a widespread non-pruritic
cities, some of which have progressed to severe, life- macropapular rash. The patient had extensive skin
threatening, and fatal toxicity.3–13 Here, we present a
case report where the concomitant use of allopurinol,
1
rituximab, and bendamustine induced fatal SJS/TEN in Department of Pharmacy, University of Wisconsin Hospital and Clinics
a patient with non-Hodgkin’s B-cell lymphoma. F6/133, Madison, WI, USA
2
Department of Pharmacy, University of Wisconsin School of Pharmacy,
Madison, WI, USA
Case report Corresponding author:
Michael J Fallon, University of Wisconsin Hospital and Clinics F6/133 600
A 78-year-old Caucasian male with no pertinent past Highland Avenue, Madison, WI 53792 United States.
medical history was newly diagnosed with diffuse large Email: [email protected]
Fallon and Heck 389

sloughing of multiple body surfaces and mucous mem- progression of symptoms, the patient requested pallia-
branes as well as fragile skin throughout the remainder tive measures and died secondary to complications of
of his body. He received supportive care and, upon SJS/TEN.
stabilization, was immediately transferred to our facil- The patient had recently started palonosetron, dexa-
ity for treatment the day of his admission. methasone, prochlorperazine, allopurinol, rituximab,
The patient was admitted to the burn surgery service and bendamustine as part of his treatment regimen
for further assessment where tissue involvement was and continued to take maintenance medications includ-
noted to include the patient’s face, anterior and poster- ing vitamin D, aspirin, levothyroxine, and lorazepam.
ior trunk regions, upper and lower extremities, oral He had no known medication allergies and had not
mucosa, ocular conjunctiva, and genitalia, all of been previously treated with allopurinol, bendamus-
which were Nikolsky’s sign positive. The Lund– tine, or rituximab.
Browder Burn calculation was used to determine the To assess the relationship of medication use to
percentage of total body surface area affected and esti- adverse effect, the patient’s Naranjo probability algo-
mated 14% involvement, consistent with a diagnosis of rithm score was calculated and supported a probable
SJS/TEN.2,14 The patient was also tachycardic, hypo- drug-induced reaction (Naranjo score ¼ 5, Table 2).15
tensive, and febrile. Allopurinol was discontinued fol- This score was obtained because the adverse event
lowing confirmation that the patient had taken the appeared after the suspected drug was administered
medication as directed for 13 days with his last reported and there were no alternative causes that could explain
dose being the day before hospital admission. the reaction, and because the reaction has been conclu-
Supportive care measures including hydration, wound sively reported previously.
debridement, systemic and topical antibiotics, ophthal- The SCORTEN (SCORe of TEN) severity of ill-
mic irrigation and lubrication, nutritional support, and ness scale was also determined and predicted a 58.3%
pain management were provided. With further mortality rate in this patient (SCORTEN score ¼ 4,
Table 3).16 The patient earned a point each for being
older than 40 years old, having an associated malig-
nancy, having serum blood urea nitrogen greater than
Table 1. Rituximab + bendamustine chemotherapy regimen. 27 mg/dL, and having greater than 10% detached or
compromised body surface. The patient’s heart rate
Dose Patient’s dose
was recorded at 116 on admission and likely would
Drug (mg/m2) (mg) Day Cycle length
have been greater than 120 had he not received fluid
Rituximab 375 700 1 28 days resuscitation prior to arrival at our facility, which
Bendamustine 90 175 2–3 28 days would given him a score of 5 with a predicted >90%
mortality rate. The SCORTEN scale has been validated

Table 2. Naranjo ADR probability scale.16

Yes No Unsure, not done Patient’s score

Are there previous conclusive reports on this reaction? +1 0 0 +1

Did the adverse event appear after the suspected drug was administered? +2 1 0 +2
Did the adverse reaction improve when the drug was discontinued or a specific +1 0 0 0
antagonist was administered?
Did the adverse reaction reappear when the drug was readministered? +2 1 0 0
Are there alternative causes (other than the drug) that could, on their own, 1 +2 0 +2
have caused the reaction?
Did the reaction reappear when placebo was given? 1 +1 0 0
Was the drug detected in the blood (or other fluids) in concentrations known to be +1 0 0 0
toxic?
Was the reaction more severe when the dose was increased or less severe when the +1 0 0 0
dose was decreased?
Did the patient have a similar reaction to the same or similar drugs in any previous +1 0 0 0
exposure?
Was the adverse event confirmed by any objective evidence? +1 0 0 0
Total score +5 (probable)
390 Journal of Oncology Pharmacy Practice 21(5)

Table 3. SCORTEN severity-of-illness index.16

Risk factor 0 1 Patient’s score

Age <40 years >40 years 1

Associated malignancy No Yes 1
Heart rate (beats/min) <120 >120 0
Serum BUN (mg/dL) <27 >27 1
Detached or compromised body surface <10% >10% 1
Serum bicarbonate (mEq/L) >20 <20 0
Serum glucose (mg/dL) <250 >250 0
Total score 4 (58.3% predicted mortality rate)

Table 4. FDA Adverse Event Reporting System TEN case reports from October 30, 2008 to October 30, 2013—unless noted all
data in parenthesis is % of TEN cases.

Allopurinol Rituximab Bendamustine

Drug (n ¼ total ADR case reports) (n ¼ 3007) (n ¼ 20,622) (n ¼ 4110)

TEN case reports (% of total ADR case reports) 134 (4.5) 19 (0.09) 14 (0.34)
Concomitant allopurinol – 4 (19.0) 6 (42.9)
Concomitant rituximab 4 (3.0) – 8 (57.1)
Concomitant bendamustine 6 (4.4) 8 (42.1) –
Concomitant allopurinol and rituximab – – 4 (28.6)
Concomitant chemotherapy other than bendamustine 10 (7.5) 5 (26.3) –
Resulting in death 49 (36.6) 5 (23.8) 4 (28.6)
Concomitant allopurinol – 0/4 2/6
Concomitant rituximab 0/4 – 0/8
Concomitant bendamustine 2/6 0/8 –
Concomitant allopurinol and rituximab – – 0/4
Concomitant chemotherapy other than bendamustine 3/10 3/5 –
Resulting in hospitalization 91 (67.9) 14 (66.7) 6 (42.9)
Concurrent SJS 45 (33.8) 1 (4.8) 3 (21.4)
Median age (range)—yeara 64 (5–94) 57 (16–77) 61 (45–70)
Male sex—% of patientsa 40.5 68.8 50.0
Geographic regiona
Americas 38 8 9
Asia 28 1 1
Europe 57 11 4
Africa, Australia, or unknown 11 1 0
SJS: Stevens–Johnson syndrome.
a
Data not reported for all cases.

for not only TEN but rather for the full continuum of similar to TEN than SJS, which is why we focused our
SJS, SJS/TEN, and TEN. analysis on TEN case reports.16 It is interesting that
To further assess risk FDA Medwatch adverse event, approximately 30% of the TEN case reports did list
case reports over a 5-year period from 2008 through concurrent SJS adverse reactions some of which may
2013 on allopurinol, bendamustine, and rituximab have been SJS/TEN overlap cases.
were examined (Table 4). SJS/TEN overlap case reports Allopurinol had the fewest total adverse drug reac-
were initially assessed but only three cases were tion reports but the highest number of TEN reaction
reported, possibly due to nomenclature confusion, reports at 134, which was seven times higher than that
while 167 TEN case reports were filed. SJS/TEN treat- reported for rituximab and approximately 10-fold
ment and mortality have been shown to be much more higher than for bendamustine. Percentage of
Fallon and Heck 391

allopurinol TEN reactions resulting in patient death deaths occurred among the FDA Medwatch TEN cases
was also the highest at 36.6%, followed by bendamus- of concomitant allopurinol and rituximab, bendamus-
tine at 28.6% and rituximab at 23.8%. tine and rituximab, or a combination of the three drugs.
Out of four TEN case reports of patients that Three of five patients that received rituximab with con-
received concomitant allopurinol, rituximab, and bend- current chemotherapy other than bendamustine died
amustine, none died; however, two out of six patients and were the majority of rituximab-related deaths.
that received concomitant allopurinol and rituximab The first of these patients received cyclophosphamide,
died. TEN reactions due to allopurinol and rituximab the second received fludarabine, cyclophosphamide,
resulted in a similar percentage of hospitalized patients doxorubicin, and vincristine, and the third received
with reactions due to bendamustine resulting in fewer cyclophosphamide, methotrexate, vincristine, and
hospitalizations. While eight of 19 rituximab TEN reac- doxorubicin. Case studies of TEN have been reported
tions occurred with concomitant bendamustine, for cyclophosphamide, fludarabine, methotrexate, and
another seven rituximab reactions occurred without doxorubicin. A black box warning for TEN is included
concomitant allopurinol, bendamustine, or non-benda- in the methotrexate package insert.
mustine chemotherapy (data not included in table). Bendamustine is a nitrogen mustard compound that
Three of 14 bendamustine reactions occurred without functions as a chemotherapeutic agent with both DNA
concomitant allopurinol or rituximab. alkylation and anti-metabolite properties. Phase II clin-
ical trial and post-marketing reports demonstrated rare
cases of severe, life-threatening skin reactions including
Discussion
SJS and TEN.12,13 To date, there are no published
Allopurinol is a xanthine oxidase inhibitor, which reports demonstrating that bendamustine alone causes
blocks uric acid formation, and is utilized as prophy- SJS, SJS/TEN, or TEN; however, a single case reported
laxis in patients with an elevated risk of hyperuricemia that single agent bendamustine caused a severe cutane-
and tumor lysis syndrome. It is generally well tolerated; ous interface drug eruption.4 In the bendamustine
however, it is known to cause hypersensitivity reactions package insert, it is noted that SJS and TEN have
including rash that may progress to more severe skin been reported with concomitant allopurinol and other
reactions including SJS, SJS/TEN, and TEN.5–8 It is of medications known to cause these severe skin
interest that 4.5% of all reported FDA Medwatch allo- reactions.12
purinol adverse effect reports were TEN reactions, a As allopurinol, bendamustine, and rituximab have
relatively large percentage. Only 12% of these cases all been known to cause severe skin reactions, questions
occurred in the setting of chemotherapy, six of which remain regarding which agents are causative when, and
were with concomitant bendamustine. It is possible that whether or not the possibility of an additive risk of SJS/
our patient may not have encountered this serious TEN when multiple drugs known to be associated with
adverse effect or may have developed a more mild to SJS/TEN are administered concomitantly. Given the
moderate case had he taken a shorter course of allopur- severity of the reaction and the high-mortality risk,
inol than 13 days. A retrospective study did show that re-challenging one or more drugs in patients to fully
immediate withdrawal of potential offending drug at elucidate the underlying cause of SJS/TEN is not
the onset of SJS/TEN symptoms decreased the risk of acceptable. FDA Medwatch data have several limita-
death.17 FDA Medwatch data do not routinely ascribe tions. There is no certainty that the reported adverse
duration of therapy but this would have been an inter- events are actually due to the drug identified, and sub-
esting contribution to our analysis. mission of reports is voluntary and dependent on a
Rituximab is a monoclonal antibody used as a che- broad variety of factors. The information from these
motherapeutic agent to target CD20 + blood cells. reports cannot be utilized to calculate adverse event
Rituximab can cause severe mucocutaneous reactions, incidence. While difficult to draw strong associations
some with fatal outcomes. Case reports have linked with these limitations and the limited number of TEN
rituximab with SJS, SJS/TEN, and TEN as well as case reports, the available Medwatch data on concomi-
paraneoplastic pemphigus, lichenoid dermatitis, and tant allopurinol, rituximab, and bendamustine use
vesiculobullous dermatitis.9–11 Our patient would be available at this time do not show additive risk.
the first patient reported to FDA Medwatch that died
secondary to a SJS/TEN reaction following allopurinol,
rituximab, and bendamustine exposure. Of course, it is
Conclusion
possible that rituximab use was underreported in While the incidence of SJS/TEN is rare, the overall
patients receiving this treatment regimen as rituximab mortality rate of patients with this adverse effect is
as a causative agent of SJS/TEN is rare, and some approximately 30%. It is important to identify symp-
would argue controversial.11 It is noteworthy that no toms and disease progression early, remove potential
392 Journal of Oncology Pharmacy Practice 21(5)

offending agents immediately, and provide optimal sup- 6. Pennell DJ, Nuan TO, O’Doherty MJ, et al. Fatal
portive care to promote recovery and reduce mortality. Stevens-Johnson syndrome in a patient on captopril
Quantifying additive risk of this rare adverse effect and allopurinol. Lancet 1984; 1: 463–466.
from use of concomitant medications associated with 7. Haur YL, Pang SM and Thamotharampillai T.
this reaction such as allopurinol, rituximab, and bend- Allopurinol-induced Stevens-Johnson syndrome and
toxic epidermal necrolysis. J Am Acad Dermatol 2008;
amustine remains a challenge.
59: 352–353.
It is important to recognize that tumor lysis syn-
8. Somkrua R, Eickman EE, SaoKaew S, et al. Association
drome is a potential serious adverse effect that must of HLA-B*5801 allele and allopurinol-induced Stevens-
be closely monitored. If allopurinol is deemed necessary Johnson syndrome and toxic epidermal necrolysis: a sys-
as tumor lysis prophylaxis in treatment regimens con- tematic review and meta-analysis. BMC Med Genet 2011;
taining rituximab and bendamustine, it is probably 12: 118–127.
rational to utilize as short of course as is clinically 9. Genentech Inc. Rituxan (package insert). South San
required with close monitoring. Consideration of Francisco: Genentech Inc, 2013.
avoidance of allopurinol in patients with low risk for 10. Lowndes S, Darby A, Mead G, et al. Stevens-Johnson
tumor lysis syndrome is likely clinically appropriate. syndrome after treatment with rituximab. Ann Oncol
2002; 13: 1948–1950.
Funding 11. Henning JS and Firoz BF. Rituxan is not associated with
Stevens-Johnson syndrome. Ann Oncol 2011; 22:
This research received no specific grant from any funding
1463–1464.
agency in the public, commercial, or not-for-profit sectors.
12. Teva Pharmaceuticals Inc. Treanda (package insert).
North Wales, PA: Teva Pharmaceuticals Inc, 2013.
Conflict of interest 13. Robinson K, Williams M, van der Jagt R, et al. Phase II
None declared. multicenter study of bendamustine plus rituximab in
patients with relapsed indolent b-cell and mantle cell
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