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1106 Part VIII: Monocytes and Macrophages Chapter 71: Inflammatory and Malignant Histiocytosis 1107

Reports for treatment of the CNS neurodegenerative syndrome regimens are curative and associated with less toxicity and improved
have been limited to case series and pilot studies. Strategies include survival. 92
oral dexamethasone, intravenous cladribine, oral all-trans retinoic acid, Options No Longer Considered Effective Treatments for LCH in
intravenous immunoglobulin, and intravenous cytarabine. 80–82 All-trans any location that have been used in the past but are no longer recom-
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retinoic acid was given at a dose of 45 mg/m daily, orally, for 6 weeks, mended include cyclosporine and interferon (IFN)-α. Extensive surgery
then 2 weeks a month for 1 year. Intravenous immunoglobulin, 400 mg/ is also not indicated. It is critical that LCH bone lesions (especially skull
2
m monthly. Some investigators have given chemotherapy along with and mandible) not be treated by excision with wide margins. Even large
the IVIG. The chemotherapy plan was prednisolone 2 mg/kg 5 days a defects may remodel to near normal architecture following resolution
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month with or without oral or IV methotrexate 20 mg/m one day every of LCH follow chemotherapy and/or curettage. Similarly, surgical resec-
2 weeks, daily oral 6-mercaptopurine 1.5 mg/kg/day, or monthly vin- tion or radiotherapy of groin or genital lesions is contraindicated as che-
2
blastine 6 mg/m /dose once monthly for a year. MRI findings were sta- motherapy can heal skin lesions.
ble, but clinical efficacy was difficult to judge as patients were reported
to have no progression in their neurologic symptoms. Intravenous cyta- COURSE AND PROGNOSIS
rabine with or without intravenous vincristine was effective in decreas-
ing neurologic symptoms and improving the MRI images in five of eight LCH patients with low-risk disease treated with vinblastine and predni-
patients who were stable for longer than 8 years. sone have a 99 percent chance of survival, but more than 50 percent fail to
Recurrent, Refractory, or Progressive Childhood Langerhans Cell be cured with initial therapy. Nearly 100 percent of these patients are ulti-
Histiocytosis mately cured of LCH, though many require multiple courses of salvage
Recurrent “Low-Risk” Organ Involvement The optimal therapy therapy. Patients with high-risk disease who do not respond adequately
for patients with relapsed or recurrent disease has not been deter- by 12 weeks of treatment now have an 87 percent chance of long-term
mined. Patients with recurrent bone disease who reoccur more than survival, but also often require salvage therapy as described earlier.
6 months after stopping vinblastine and prednisone can benefit from
treatment with a “reinduction” of intravenous vinblastine, weekly, and PERMANENT CONSEQUENCES
daily oral prednisone for 6 weeks. If there is no active disease, or at least
very little evidence of active disease, then treatment can be changed to AND LATE EFFECTS OF TREATMENT
every 3 weeks with the addition of oral methotrexate weekly and Disease-associated sequelae remain a major challenge for patients with
oral 6-mercaptopurine nightly. Three approaches (1) intravenous clad- LCH, with risk of complications increasing with multisystem, high-risk,
ribine, (2) intravenous vincristine and intravenous cytarabine, and (3) and prolonged duration of active disease. Children with low-risk organ
intravenous clofarabine are effective regimens for patients with recur- involvement (skin, bones, lymph nodes, or pituitary gland) treated for
rent bone disease. 83–85 6 months have a 24 percent chance of developing long-term sequelae.
93
A phase II trial of oral thalidomide for LCH patients (10 low- Those with DI are at risk for panhypopituitarism and should be mon-
risk patients; 6 high-risk patients) who failed primary and at least one itored carefully for adequacy of growth and development. In a retro-
secondary regimen showed a complete response in 4 of 10 and partial spective review of 141 patients with LCH and DI, 43 percent developed
responses in 3 of 10 low-risk patients. However, dose-limiting toxicities growth hormone deficiency. The 5- and 10-year risks of growth hor-
54
and extraordinary cost limit the overall usefulness of thalidomide. 70 mone deficiency among children with LCH and DI were 35 percent and
Recurrent High-Risk Organ Involvement A new treatment plan 54 percent, respectively. There was no increased reactivation of LCH in
is indicated when a patient with multisystem involvement progresses patients who received replacement growth hormone compared to those
after 6 weeks of standard treatment, or has not had a partial response who did not.
by 12 weeks. Data from the LCH-III study showed only 57 percent sur- Patients treated before 2000 with multisystem involvement had a
vival for this group. A prospective trial with cladribine (5 mg/m per 71 percent incidence of long-term problems. 93,94 Hearing loss has been
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day, intravenously, for 5 days monthly for 6 months) had high rates of found in 13 percent of children treated for LCH. Neurologic symp-
response in patients with recurrent and refractory low-risk, but not toms secondary to vertebral compression of cervical lesions have been
high-risk, LCH. Another regimen for patients with refractory high- reported in LCH patients with spinal lesions. Cognitive defects and MRI
85
risk LCH is treatment with a highly intensive strategy based on acute abnormalities may develop in some long-term survivors with CNS-risk
myelogenous leukemia protocols. Treatment with high-dose cladribine skull lesions. Some patients have markedly abnormal cerebellar func-
95
(9 mg/m per day) coupled with cytarabine (1 g/m per day) for 5 days tion and behavior abnormalities, while others have subtle deficits in
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for at least 2 months resulted in increased overall survival and cure in brain stem–evoked potentials and short-term memory. 96
previously refractory patients. However, there was also a relatively high Orthopedic problems from lesions of the spine, femur, tibia, or
treatment-related mortality. Institutional case series with intravenous humerus may be seen in 20 percent of patients. These problems include
86
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clofarabine (25 mg/m /day for 5 days/month) have promising results in vertebral collapse or instability of the spine that may lead to scoliosis,
patients who have failed multiple previous strategies with manageable and facial or limb asymmetry.
toxicities. 87–89 There is considerable interest in use of the BRAF inhibi- Diffuse pulmonary disease may result in poor lung function
tors for treatment of refractory and recurrent LCH in patients with the with higher risk for infections and decreased exercise tolerance. These
BRAF V600E mutation. There are pediatric and phase I studies for several patients should be followed with pulmonary function testing including
anti-BRAF compounds. Concern for more widespread use in the setting the diffusing capacity of carbon monoxide and ratio of residual volume
of pediatric LCH is tempered by of the toxicity profile that includes high to total lung capacity. 45
90
incidence of squamous cell carcinoma in melanoma patients. There Liver disease may lead to sclerosing cholangitis which responds
is only one published report on use of oral vemurafenib for two adult to chemotherapy in only 25 percent of cases and liver transplantation
patients who had LCH and ECD with positive responses. 91 usually is indicated. 41
Allogeneic hematopoietic stem cell transplantation (AHSCT) has Dental problems characterized by loss of teeth have been sig-
been used for patients with multisystem high-risk organ involvement nificant for some patients, usually related to overly aggressive dental
that is refractory to chemotherapy. Reduced-intensity conditioning surgery. 93

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