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Tracey Ngo, PharmD Student III
APPE-R2
Palifermin associated with Hand Foot Syndrome
Mucositis of the gastrointestinal tract is one of the most common and dose-limiting side
effects for patients going through intense chemotherapy and stem cell transplant. Prior to 2004,
there was not a single agent used for the prevention of oral mucositis and the only treatments
available were for symptomatic relief with oral care, topical agents and ice packs.6 At the end of
2004, the FDA approved a recombinant human keratinocyte growth factor called palifermin
(Kepivance) to prevent oral mucositis. 2,3,6 Additionally, this growth factor was found to
decrease the incidence, duration, and severity of oral mucositis in patients with hematologic
malignancies undergoing intensive chemotherapy and radiation followed by autologous stem cell
transplantation (AutoSCT).2,3,6 Palifermin stimulates proliferation, migration, and differentiation
of the epithelial cells on the skin, oral mucosa, gastrointestinal tract, lungs, and genitourinary
tract.4 However, as with any medications, palifermin comes with unwanted side effects.
Potential skin reactions include rash, pruritus, and erythema.4 There are multiple case reports of
skin hyperpigmentation associated with the use of palifermin, as well as a case of palmar-plantar
erythrodysesthesia (PPE).6
PPE is also known as hand foot syndrome (HFS) and chemotherapy-induced acral
erythema; these terms can be used interchangeably. Patients with HFS often complain of painful
red lesions on the palms of their hands and/or the soles of their feet (palmoplantar regions).1
Although HFS is often not life-threatening, it does have a huge impact on the patient’s quality of
life. HFS might also lead to a dose reduction or disruption of the chemotherapy agents, which
would limit the anticancer effect of the therapy.1,5 HFS is a common side effect of pyrimidine
analogs (cytarabine, 5-Fluorouracil, capecitabine), doxorubicin, and docetaxel. Lower incidence
of HFS occurs with the use of paclitaxel, hydroxyurea, methotrexate, 6-mercaptopurine,
cyclophosphamide, cisplatin, daunorubicin, etoposide, and irinotecan.1 In general, patients
would complain of pain and sensitivity to touch after the initial weeks of starting the above
therapy.1 Within a few days, the symptoms would worsen with swelling, burning pain, and
redness mainly found on the palmoplantar regions, which may progress to blistering, ulceration
or erosion of the affected area.1 In severe cases, it may affect the intertriginous areas.1
Improvement is seen within weeks of onset of symptoms and scaling of the affected area
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signifies the healing of the lesions.1 Once the therapy is discontinued, permanent damage is
rarely observed.1
Although PPE seldom causes permanent damage, it is still problematic since it can
decrease the patient’s quality of life and affect their activities of daily living (ADL) such as
showering, walking, and hand movement. Keijzer and van de Loosdrecht proposed a mechanism
for palifermin-induced PPE in their 2007 study. They hypothesized that palifermin enhances the
proliferation of epithelial cells thereby increasing the susceptibility of these cells to the cytotoxic
effects of chemo agents, like cytarabine; one of these toxic effects is PPE. The first case report
of PPE after palifermin use was observed in a 60 year-old patient with recurrent diffuse large Bcell non-Hodgkin lymphoma after being treated with palifermin prior to his BEAM regimen and
AutoSCT. Within a day of the palifermin infusion, the patient noticed a diffuse itchy skin rash.3
A few days after, the rash became painful, swollen, and red in the palmoplantar region followed
by formation of blisters and lesions on the skin.3
PPE was also observed in a 46 year-old male with acute myeloid leukemia (AML)
starting his palifermin administration with the first dose four days prior to his high-intensity reinduction chemotherapy regimen, bigICE. Palifermin was administered because a grade 4
mucositis (based on the World Health Organization criteria) developed with the induction of
bigICE treatment. Within 12 hours of the first palifermin dose, he complained of erythema, pain,
and an acute burning sensation in his hands. These symptoms progressively worsened over the
next few days with the formation of pallor vesicles, edema, and erythema on the top and bottom
surfaces of the hands and fingers. The redness and pain spread to other parts of his body such as
the arms, shoulders, neck, and back without affecting the feet. He did require opioid treatment to
help with the pain. Lesions and erosions developed over the next few weeks, but within a month
of symptom onset, the skin proceeded to heal without noticeable damage. However, his last
three doses of palifermin scheduled to be given post chemotherapy was cancelled due to the
development of PPE. Most of the skin reactions are mainly seen in the palmoplantar regions. 6
One proposed mechanism is that said region has higher concentration of receptors thereby
increasing its susceptibility to the adverse effect of the medication.6
The first time these cutaneous reactions associated with palifermin use has been
supported by histological analysis was in the case of a 57 year-old male with multiple myeloma
after treatment with palifermin four days prior to his melphalan conditioning regimen for an
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AutoSCT. After the third dose of palifermin, he developed “an intense macular erythematous
eruption” without pruritus that affected his intertriginous regions such as his groin, axillary, and
neck areas. The reaction resolved within three days of the palifermin administration with the
help of systemic and topical corticosteroids. This particular reaction was due to palifermin and
not other causes since the onset of the skin eruption coincided with the administration of the
palifermin. The histology of the affected area demonstrated the presence of large keratinocytes
suggestive of the direct impact of palifermin on the epithelial cell proliferation and
differentiation, increasing the risk for PPE and other cutaneous reactions such as flexural
erythematous development.2
City of Hope, one of the premier cancer institutes in the nation, has also documented
some cutaneous reactions associated with the combination of palifermin and chemotherapeutic
use. Although there were numerous observed cases relating to the use of palifermin, this paper
will specifically focus on the following three patients. The first case involves JS, a 48 year-old
female with a history of AML admitted for a matched-related allogeneic stem cell transplant
(AlloSCT). She received three doses of Palifermin prior to her conditioning regimen consisting
of total body irradiation (TBI) and etoposide. She developed skin irritation, erythema, and
pruritus of the hand, chest, and face after her first two doses of palifermin. Ten days later, her
condition improved with the rash localized primarily to the chest area. The chest area improved
two weeks after the onset of the symptoms. Palifermin is said to be the cause of the skin reaction
given that the rash started within a day or two of administration and prior to any of the
conditioning regimen. Another case involved CW, a 27 year-old female with a history of AML
admitted for an unmatched unrelated AlloSCT. Her palifermin doses were given prior to the
conditioning regimen consisting of cyclophosphamide and TBI. A week after receiving
palifermin, cyclophosphamide, and TBI, the patient developed a severe, macular, papular,
pruritic rash on her arms and feet. Within a few days, the rash developed into a severe skin
eruption with swelling and erythema in the palmoplantar regions. The erythema and swelling of
the hands extended to the wrists and she noticed her fingers and feet were tender to touch. On
day seven, she also noticed discomfort in the groin and axillary areas. Her condition started
improving on day 21 and complete resolution of the rash and swelling was noted on day 23. Her
treatment consisted of ice packs and topical agents such as granulex, silvadene, lidocaine, and
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morphine cream; the ice pack relieved symptoms more than the topical cream. She also received
hydromorphone drip, which helped to control her pain.
MM, a 38 year old female with acute lymphoblastic leukemia is currently being followed
for a possible palifermin-associated HFS. She received three doses of palifermin (60mcg/kg IV
for each dose) prior to the conditioning regimen consisting of TBI and etoposide. She also
received a dose of 180mcg/kg IV palifermin after the administration of her conditioning regimen
but before day -1 of her AlloSCT. On day 14, after receiving palifermin and the conditioning
regimen, she started experiencing slight sensitivity to touch on her right thumb and pruritus on
her right leg. On day 17, both of her hands were swollen with minimal swelling on her feet. On
day 18, she complained that her palms were very itchy, painful, red, and sensitive to touch—her
pain was exacerbated with exposure to hot water/showers. She also had some extension of the
pain in the medial aspect of her right forearm up to the axillary region without obvious erythema,
warmth or swelling. Subsequent ultrasound and x-ray were negative for deep vein thrombosis.
On day 22, her palms were still swollen and itchy, but the skin color is darker red (no longer
bright red like previous days). She was given silvadene, lidocaine, benadryl cream and radiogel
to help soothe the pain and pruritus, but the ice pack was the most efficacious. She was also
given albumin and furosemide for the swelling in her hands and her morphine drip was adjusted
to help with the pain associated with HFS. Due to the onset of symptoms, it is hard to identify
the cause of the HFS. There could be multiple contributors in this situation such as etoposide,
TBI, and/or palifermin. MM will be followed in the subsequent days to see if her skin condition
will worsen or improve.
Currently, there are no guidelines for the proper treatment of HFS. Most
recommendations are based on expert opinions and clinical experience. Patients undergoing a
chemotherapeutic regimen or stem cell transplantation with high incidence of HFS with or
without palifermin should be considered for prophylaxis treatment. Prior to treatment, patients
should avoid putting pressure/stress to the skin such as heavy lifting/carrying, long walks,
wearing tight-fitted shoes, gloves, or clothes, and heat exposure. It is recommended for patients
to use moisturizing lotion on a regular basis and to rinse off sweat with lukewarm water.
Patients should receive a clinical examination of the extremities to assess for risk factors such as
the presence of hyperkeratosis, eczema, fungal disease, and any uneven distribution of pressure,
then address it accordingly with appropriate foot care, dermatological referral, or orthopedic
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treatment of mal-alignment. A reduction in the frequency and severity of HFS was observed
when the cooling method was applied during treatment; the mechanism is thought to be induced
vasoconstriction, which impairs circulation and decreases the exposure of the hands and feet to
the chemotherapy agent.5
Treatment of HFS mainly consists of modifications such as dose reduction or interruption
of chemotherapeutic regimen. Topical agents have also been utilized depending on the
symptoms that are presented. 2% lidocaine gel is efficacious in alleviating pain and sensitivity to
touch in the early stages of HFS because it is easier to absorb prior to the onset of keratinization.7
After keratinization, topical agents containing 5–10 % salicylic acid or 10–20 % urea can be
used. If inflammation occurs, topical steroids such as mometasone, clobetasol may be given.
Baths containing potassium permanganate dye or tanning agents may be effective for oozing
lesions. Using ice packs on the hands and feet three to four times daily to avoid the development
of excessive warmth was seen to be one of the more effective methods to reduce pain associated
with HFS. Series of cases have reported that pyridoxine (vitamin B6) is effective in reducing the
duration and intensity of symptoms and has also been used for treatment of HFS dosed at 50 to
300 mg a day.1 The main goal of HFS treatment is to improve the patient’s quality of life and
prevent the discontinuation of life-saving chemotherapeutic agents.
Although HFS is a non life-threatening skin reaction, it can greatly impact the patients
physically, emotionally, and socially. Therefore, more research needs to be done to determine
the true mechanism of palifermin-induced PPE. Clinical trials that look at the incidence of PPE
prior to and after introduction of palifermin, look at the different ranges of side effects associated
with palifermin use especially in combination with chemotherapeutic agents with high incidence
of cutaneous reactions, and look at the benefit of prophylactic versus symptomatic treatments are
needed to better understand this medication. Currently, there is no strong evidence to limit the
use of palifermin, but hopefully more research providing evidence of palifermin-associated side
effects will help clinicians to better weigh risks and benefits of its use. For now, clinicians will
continue using palifermin for mucositis prophylaxis and treat HFS based on symptom
manifestation once it occurs.
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References:
1. Degen A, Alter M, Schenck F, et al. The hand-foot-syndrome associated with medical
tumor therapy - classification and management. J Dtsch Dermatol Ges. Sep;8(9):652661.
2. Diaz Ley B, Guhl G, Eguren Michelena C, Fernandez Herrera J, Fraga J, Garcia Diez A.
Flexural cutaneous eruption due to palifermin. Br J Haematol. Feb 2008;140(4):464-465.
3. Keijzer A, Huijgens PC, van de Loosdrecht AA. Palifermin and palmar-plantar
erythrodysesthesia. Br J Haematol. Mar 2007;136(6):856-857.
4. King B, Knopp E, Galan A, Nuovo G, Tigelaar R, McNiff J. Palifermin-associated
papular eruption. Arch Dermatol. Feb 2009;145(2):179-182.
5. Lacouture ME, Wu S, Robert C, et al. Evolving strategies for the management of handfoot skin reaction associated with the multitargeted kinase inhibitors sorafenib and
sunitinib. Oncologist. Sep 2008;13(9):1001-1011.
6. Milne O, Cutts B, McLean C, Gin D. Palifermin-induced acral erythrodysaesthesia
variant in the treatment of acute myeloid leukaemia. Australas J Dermatol. Feb;52(1):5961.
7. Saha R, Jain S, Naithani R, Kapoor G. Chemotherapy-induced palmoplantar
erythrodysesthesia in a child with Burkitt lymphoma. Pediatr Blood Cancer. Oct
2009;53(4):682.
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