Page 847 - Hematology_ Basic Principles and Practice ( PDFDrive )

730 Part VI Non-Malignant Leukocytes

approach emphasizes the need for treatment protocols based on Histiocyte Society has stratified patients with LCH into “low-risk”
careful prognosis-based risk stratification. Whether more intense (LR) and “high-risk” (HR) groups based on outcomes related to
upfront therapy in lower risk patients can reduce disease sequelae, the extent and location of the LCH lesions. LR patients include
such as DI, CNS degeneration, sclerosing cholangitis, or disease patients with skin, bone, lymph node, and pituitary involvement.
recurrence, is currently under evaluation. For the majority of patients Patients with liver, spleen, or BM involvement usually have a worse
with localized or limited systemic disease, the goal of therapy should prognosis and are considered higher risk. Children with lung LCH,
be minimizing loss of function and preventing cosmetic deformity. without involvement of other HR organs, are generally not consid-
Seborrhea-like dermatitis of the scalp may improve with use of a ered to be HR. Additionally, LR patients believed to have lesions
selenium- or phenol-based shampoo. Topical steroids can be effective, that may increase their future risks of CNS degenerative disease
but prolonged exposure or use on the face should be avoided. Topical (lesions within the CNS, skull base, or facial bones) are designated as
nitrogen mustard has been used for problematic focal skin lesions. In “CNS risk”.
patients with particularly refractory and extensive skin involvement, Alternative treatment has not been standardized for patients with
psoralen ultraviolet A can be effective. These topical therapies have recurrent or refractory disease. Patients with recurrent disease (i.e.,
not been studied in clinical trials. disease that reappears after a period of remission) often respond well
to the drugs with which they initially were treated. Several studies,
including an international phase II trial, have demonstrated signifi-
Surgery and Radiotherapy cant activity of 2-chlorodeoxyadenosine (2-CdA) against recurrent
and refractory LCH. In addition, the combination of 2-CdA and
Patients with disease involving a single bone can usually be managed high-dose cytarabine has been used in refractory, high-risk patients.
with local therapy. This most often involves surgical curettage for However, recent reports suggest that clofarabine may be a superior
patients whose lesions are in easily accessible, noncritical locations. agent for salvage treatment of refractory LCH compared with histori-
Complete “cancer operation” resections are not considered necessary cal experience (although no direct comparison has been conducted).
and should be avoided to reduce cosmetic and orthopedic deformi- Finally, a recent report, by Simko et al has demonstrated that upfront
ties, as well as loss of function. Local soft tissue disease (e.g., scalp, use of cytarabine monotherapy is associated with excellent response
thymus, lymph nodes) generally recurs despite surgery; thus, addi- rates, and may avoid the toxicities of prednisone/vinblastine-based
tional treatment with antiinflammatory or cytoreductive drugs is regimens.
usually required. Because of concerns about the development of
secondary malignancies, systemic therapy is usually favored over
radiation. However, local radiotherapy is indicated under certain Long-Term Follow-up
circumstances; for example, when patients are at risk for visual or
hearing loss, skeletal deformity, spinal cord injury, or severe pain Retrospective analysis of “CNS risk” patients treated with only
when systemic therapy is not rapidly effective. surgery, steroid injection, radiation therapy, or a single chemotherapy
drug have a 40% incidence of DI. If they receive vinblastine and
prednisone for 6 months the incidence of DI is 20%. Complications
Chemotherapy of developing DI include a significant incidence of anterior pituitary
hormone deficiencies or neurodegenerative syndrome. Patients with
Historically, drugs used in therapy for classic malignant diseases have neurodegenerative syndrome may have ataxia, dysarthria, dysmetria,
been used for the systemic or local treatment of LCH. A variety and learning and behavior difficulties. The diagnosis may be aided
of drugs, including vinblastine, vincristine, cytarabine, nitrogen by brain MRI, in which T2 hyperintense signals in the cerebellum,
mustard, cyclophosphamide, procarbazine, chlorambucil, etoposide, basal ganglia, or pons may be present, but such abnormalities do
methotrexate, corticosteroids, and 6-mercaptopurine (6-MP), not always correlate with clinical disease or vice versa. Treatment
have been used, alone or in combination, with variable success. with intravenous immunoglobulin (IVIG) or low-dose cytarabine has
Therapeutic advances for LCH in recent years have largely come from anecdotally resulted in stabilization of these symptoms.
international cooperative trials conducted by the Histiocyte Society. A retrospective analysis by Willis et al of 71 patients from a single
The Histiocyte Society is currently opening the next international institution followed for a median of 8.1 years from diagnosis revealed
trial, LCH-IV, which has strata allowing for the enrollment of all the presence of significant late sequelae in 64% of patients followed
patients with LCH, either as a treatment or as a registry study. For for more than 3 years. Skeletal defects were found in 42%, dental
patients not enrolled on LCH-IV, detailed treatment recommenda- problems in 30%, DI in 25%, growth failure in 20%, sex hormone
tions are available on the Histiocyte Society’s website (http://www deficiency in 16%, hypothyroidism in 14%, hearing loss in 16%, and
.histio.org). CNS dysfunction in 14%. The risk of malignancy in patients with
A reasonable therapeutic approach to systemic therapy is to LCH undergoing radiation and chemotherapy is well documented.
observe patients with limited, single-system disease who respond to Thus judicious use of radiotherapy, avoidance of potentially carcino-
local (i.e., surgery, radiation) or nonsystemic (i.e., topical steroids) genic chemotherapeutic agents, and good supportive care are recom-
therapy and look for signs of disease resolution. If persistent symp- mended. Leukemia in LCH patients treated with etoposide as a single
tomatic lesions or evidence of progressive disease is seen, systemic agent and in combination with other agents has been reported.
treatment should be pursued. Patients with disease that is localized Because etoposide was not shown to be any more effective than
to skin, bone, and lymph nodes (defined as “nonrisk” organs) gener- vinblastine in both the LCH-I and LCH-II trials for patients without
ally have a good prognosis and may require only minimal treatment. risk organ involvement, there does not appear to be reason to include
Extensive refractory skin disease may warrant systemic therapy with this leukemogenic agent in the treatment of these patients with newly
low-dose oral methotrexate, vinblastine–prednisone, or low-dose diagnosed LCH.
cytarabine, or with topical therapy such as nitrogen mustard. Another serious late effect of LCH is sclerosing cholangitis, which
Multisystem disease or multifocal bony disease usually warrants may lead to secondary biliary cirrhosis and liver failure. Sclerosing
treatment with systemic chemotherapy. The current standard of care cholangitis may develop years after successful therapy for LCH and
is a risk-adapted approach, largely using vinblastine, prednisone, and does not typically signify disease recurrence. The only successful
6-MP, based on the LCH-III trial. This approach has evolved in treatment of sclerosing cholangitis has been liver transplantation.
a stepwise fashion from previous multicenter trials conducted by Other late complications of LCH are pulmonary cyst formation,
international groups (DAL-HX 83/90 protocols [Austria, Germany, fibrosis, and chronic pneumothoraces. No effective treatment is avail-
Switzerland, The Netherlands], LCH-I, and LCH-II). All of these able, and progression to cor pulmonale and respiratory failure may
protocols were risk adapted and were based on different combinations occur. Lung transplantation has been used for treatment of such
of prednisone, vinblastine, etoposide, methotrexate, and 6-MP. The patients. Thus, all patients with LCH require long-term follow up.