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

sloughing of multiple body surfaces and mucous mem-
branes as well as fragile skin throughout the remainder
of his body. He received supportive care and, upon
stabilization, was immediately transferred to our facil-
ity for treatment the day of his admission.
The patient was admitted to the burn surgery service
for further assessment where tissue involvement was
noted to include the patient’s face, anterior and poster-
ior trunk regions, upper and lower extremities, oral
mucosa, ocular conjunctiva, and genitalia, all of
which were Nikolsky’s sign positive. The Lund–
Browder Burn calculation was used to determine the
percentage of total body surface area affected and esti-
mated 14% involvement, consistent with a diagnosis of
SJS/TEN.2,14 The patient was also tachycardic, hypo-
tensive, and febrile. Allopurinol was discontinued fol-
lowing confirmation that the patient had taken the
medication as directed for 13 days with his last reported
dose being the day before hospital admission.
Supportive care measures including hydration, wound
debridement, systemic and topical antibiotics, ophthal-
mic irrigation and lubrication, nutritional support, and
pain management were provided. With further
Table 1. Rituximab + bendamustine chemotherapy regimen.
Dose Patient’s dose
Drug (mg/m2) (mg) Day Cycle length
Rituximab 375 700 1 28 days
Bendamustine 90 175 2–3 28 days
progression of symptoms, the patient requested pallia-
tive measures and died secondary to complications of
SJS/TEN.
The patient had recently started palonosetron, dexa-
methasone, prochlorperazine, allopurinol, rituximab,
and bendamustine as part of his treatment regimen
and continued to take maintenance medications includ-
ing vitamin D, aspirin, levothyroxine, and lorazepam.
He had no known medication allergies and had not
been previously treated with allopurinol, bendamus-
tine, or rituximab.
To assess the relationship of medication use to
adverse effect, the patient’s Naranjo probability algo-
rithm score was calculated and supported a probable
drug-induced reaction (Naranjo score ¼ 5, Table 2).15
This score was obtained because the adverse event
appeared after the suspected drug was administered
and there were no alternative causes that could explain
the reaction, and because the reaction has been conclu-
sively reported previously.
The SCORTEN (SCORe of TEN) severity of ill-
ness scale was also determined and predicted a 58.3%
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
27 mg/dL, and having greater than 10% detached or
compromised body surface. The patient’s heart rate
was recorded at 116 on admission and likely would
have been greater than 120 had he not received fluid
resuscitation prior to arrival at our facility, which
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
SJS, SJS/TEN, and TEN.
To further assess risk FDA Medwatch adverse event,
case reports over a 5-year period from 2008 through
2013 on allopurinol, bendamustine, and rituximab
were examined (Table 4). SJS/TEN overlap case reports
were initially assessed but only three cases were
reported, possibly due to nomenclature confusion,
while 167 TEN case reports were filed. SJS/TEN treat-
ment and mortality have been shown to be much more
similar to TEN than SJS, which is why we focused our
analysis on TEN case reports.16 It is interesting that
approximately 30% of the TEN case reports did list
concurrent SJS adverse reactions some of which may
have been SJS/TEN overlap cases.
Allopurinol had the fewest total adverse drug reac-
tion reports but the highest number of TEN reaction
reports at 134, which was seven times higher than that
reported for rituximab and approximately 10-fold
higher than for bendamustine. Percentage of
Fallon and Heck
allopurinol TEN reactions resulting in patient death
was also the highest at 36.6%, followed by bendamus-
tine at 28.6% and rituximab at 23.8%.
Out of four TEN case reports of patients that
received concomitant allopurinol, rituximab, and bend-
amustine, none died; however, two out of six patients
that received concomitant allopurinol and rituximab
died. TEN reactions due to allopurinol and rituximab
resulted in a similar percentage of hospitalized patients
with reactions due to bendamustine resulting in fewer
hospitalizations. While eight of 19 rituximab TEN reac-
tions occurred with concomitant bendamustine,
another seven rituximab reactions occurred without
concomitant allopurinol, bendamustine, or non-benda-
mustine chemotherapy (data not included in table).
Three of 14 bendamustine reactions occurred without
concomitant allopurinol or rituximab.
Discussion
Allopurinol is a xanthine oxidase inhibitor, which
blocks uric acid formation, and is utilized as prophy-
laxis in patients with an elevated risk of hyperuricemia
and tumor lysis syndrome. It is generally well tolerated;
however, it is known to cause hypersensitivity reactions
including rash that may progress to more severe skin
reactions including SJS, SJS/TEN, and TEN.5–8 It is of
interest that 4.5% of all reported FDA Medwatch allo-
purinol adverse effect reports were TEN reactions, a
relatively large percentage. Only 12% of these cases
occurred in the setting of chemotherapy, six of which
were with concomitant bendamustine. It is possible that
our patient may not have encountered this serious
adverse effect or may have developed a more mild to
moderate case had he taken a shorter course of allopur-
inol than 13 days. A retrospective study did show that
immediate withdrawal of potential offending drug at
the onset of SJS/TEN symptoms decreased the risk of
death.17 FDA Medwatch data do not routinely ascribe
duration of therapy but this would have been an inter-
esting contribution to our analysis.
Rituximab is a monoclonal antibody used as a che-
motherapeutic agent to target CD20 + blood cells.
Rituximab can cause severe mucocutaneous reactions,
some with fatal outcomes. Case reports have linked
rituximab with SJS, SJS/TEN, and TEN as well as
paraneoplastic pemphigus, lichenoid dermatitis, and
vesiculobullous dermatitis.9–11 Our patient would be
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
possible that rituximab use was underreported in
patients receiving this treatment regimen as rituximab
as a causative agent of SJS/TEN is rare, and some
would argue controversial.11 It is noteworthy that no
391
deaths occurred among the FDA Medwatch TEN cases
of concomitant allopurinol and rituximab, bendamus-
tine and rituximab, or a combination of the three drugs.
Three of five patients that received rituximab with con-
current chemotherapy other than bendamustine died
and were the majority of rituximab-related deaths.
The first of these patients received cyclophosphamide,
the second received fludarabine, cyclophosphamide,
doxorubicin, and vincristine, and the third received
cyclophosphamide, methotrexate, vincristine, and
doxorubicin. Case studies of TEN have been reported
for cyclophosphamide, fludarabine, methotrexate, and
doxorubicin. A black box warning for TEN is included
in the methotrexate package insert.
Bendamustine is a nitrogen mustard compound that
functions as a chemotherapeutic agent with both DNA
alkylation and anti-metabolite properties. Phase II clin-
ical trial and post-marketing reports demonstrated rare
cases of severe, life-threatening skin reactions including
SJS and TEN.12,13 To date, there are no published
reports demonstrating that bendamustine alone causes
SJS, SJS/TEN, or TEN; however, a single case reported
that single agent bendamustine caused a severe cutane-
ous interface drug eruption.4 In the bendamustine
package insert, it is noted that SJS and TEN have
been reported with concomitant allopurinol and other
medications known to cause these severe skin
reactions.12
As allopurinol, bendamustine, and rituximab have
all been known to cause severe skin reactions, questions
remain regarding which agents are causative when, and
whether or not the possibility of an additive risk of SJS/
TEN when multiple drugs known to be associated with
SJS/TEN are administered concomitantly. Given the
severity of the reaction and the high-mortality risk,
re-challenging one or more drugs in patients to fully
elucidate the underlying cause of SJS/TEN is not
acceptable. FDA Medwatch data have several limita-
tions. There is no certainty that the reported adverse
events are actually due to the drug identified, and sub-
mission of reports is voluntary and dependent on a
broad variety of factors. The information from these
reports cannot be utilized to calculate adverse event
incidence. While difficult to draw strong associations
with these limitations and the limited number of TEN
case reports, the available Medwatch data on concomi-
tant allopurinol, rituximab, and bendamustine use
available at this time do not show additive risk.
Conclusion
While the incidence of SJS/TEN is rare, the overall
mortality rate of patients with this adverse effect is
approximately 30%. It is important to identify symp-
toms and disease progression early, remove potential
392
offending agents immediately, and provide optimal sup-
portive care to promote recovery and reduce mortality.
Quantifying additive risk of this rare adverse effect
from use of concomitant medications associated with
this reaction such as allopurinol, rituximab, and bend-
amustine remains a challenge.
It is important to recognize that tumor lysis syn-
drome is a potential serious adverse effect that must
be closely monitored. If allopurinol is deemed necessary
as tumor lysis prophylaxis in treatment regimens con-
taining rituximab and bendamustine, it is probably
rational to utilize as short of course as is clinically
required with close monitoring. Consideration of
avoidance of allopurinol in patients with low risk for
tumor lysis syndrome is likely clinically appropriate.
Funding
This research received no specific grant from any funding
agency in the public, commercial, or not-for-profit sectors.
Conflict of interest
None declared.
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