Inclusion Criteria:
* Prior diagnosis of Langerhans Cell Histiocytosis (stratum 1) or LCH-related disorder (stratum 2) established by standard diagnostic criteria and confirmed histologically.
* Evidence of active disease (histological confirmation of reactivation or progression is not required).
* Performance Score \> 70% (use Lansky score for age \< 16 and Karnofsky score for age = \>16).
* Patients of all ages will be eligible.
* Provide signed written informed consent.
* In stratum 1, patients must have failed one prior systemic chemotherapy regimen. In stratum 2, RDD patients must have failed treatment with corticosteroid. ECD patients who have confirmed BRAF V600E mutation must have failed treatment with a BRAF inhibitor or are not considered to be eligible for such treatment.
* There is no limitation of amount or the type of prior therapy or drugs.
* Female patients of childbearing potential must have a negative serum pregnancy test within 14 days prior to enrollment. Male and female patients must use an effective contraceptive method during the study and for a minimum of 6 months after study treatment.
* Capable of understanding the investigational nature, potential risks and benefits of the study, and able to provide valid informed consent.
* Participants must have adequate marrow functions as defined below, except those with involvement of hematopoietic system for whom these criteria can be waived:
* Absolute neutrophil count ≥ 750 cells/µL
* Platelets ≥75,000/µL
* Participants must have adequate organ functions as defined below:
* Total bilirubin ≤ 2.5x institutional upper limit of normal
* AST (SGOT)/ALT (SGPT) \< 2.5 X institutional upper limit of normal unless it is related to involvement by LCH
* Adequate renal function defined as:
* Pediatric Population (patients \< 18 years): Creatinine within normal limits or calculated creatinine clearance greater than or equal to 90 ml/min/1.73 m2 as calculated by the Schwartz formula for estimated glomerular filtration rate (GFR) where GFR (ml/min/1.73 m2) = k x Height (cm)/serum creatinine (mg/dl). k is a proportionality constant which varies with age and is a function of urinary creatinine excretion per unit of body size; 0.45 up to 12 months of age; 0.55 children and adolescent girls; and 0.70 adolescent boys.
* Adult Population (patients \>= 18 years): Serum creatinine less than or equal to 1.0 mg/dL; if serum creatinine \>1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be \>60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.203 x (0.742 if patient is female) x (1.212 if patient is black), where serum creatinine is measured in mg/dL.
* Alkaline phosphatase ≤ 2.5 x institutional upper limit of normal
Exclusion Criteria:
* Participants who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier. Corticosteroid treatment is allowed.
* Participants may not be receiving any other investigational agents targeting Histiocytosis.
* Clofarabine is excreted primarily by the kidneys. Therefore, drugs with known renal toxicity (e.g.vancomycin, amphotericin B, acyclovir, cyclosporin, methotrexate, tacrolimus) should be avoided to the extent possible during the 5 days of clofarabine treatment in each cycle or, if required, administered cautiously and with close monitoring.
* Use of alternative medications (e.g., herbal or botanical that could interfere with clofarabine) is not permitted during the entire study period.
* Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
* Pregnant women are excluded from this study because clofarabine is a nucleoside analog with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with clofarabine, breastfeeding should be discontinued if the mother is treated with clofarabine. These potential risks may also apply to other agents used in this study.
* Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin.
* Patients with a history of prior hematopoietic stem cell transplantation (HSCT), elevated conjugated serum bilirubin at study entry, uncontrolled systemic fungal, bacterial, or other infection, a history of hepatitis B or C infection or a history of cirrhosis.
* Individuals who are known to be HIV-positive on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with clofarabine. In addition, these individuals are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
