# Presentation: 738716

## Myelodysplastic, Myeloproliferative, and Histiocytic Disorders

**Kenneth McClain M.D. Ph.D.**
**Texas Children’s Cancer Center**
**Houston, TX**

## Disclosure Information

**Own common stock of Johnson & Johnson Co.**
**No discussion of unlabeled uses******=New material not in syllabus***

## What is Myelodysplastic Syndrome (MDS)or... When Do Blasts in the Marrow Not = Leukemia?

**Pediatric version of WHO Criteria for MDS**
**Absence of AML cytogenetic findings**
**Two or more of the following:****Sustained cytopenia****Dysplasia in 2 cell lines****Clonal cytognenetic abnormality (5q-, monosomy 7)****5-19% Blasts (>20% Blasts = AML)**

## MDS Can Become AML,But is not AML a priori

**May need several marrow exams to establish diagnosis of MDS vs. AML**
**Incidence of MDS ~ 1.5 per million****10-20% become AML**

## Pediatric MDS Classification

**Three major categories:****1. Adult-Type Myelodysplastic Syndromes****2. Down Syndrome with abnormal    ****	****megakaryocyte proliferation****3. Myelodysplastic/Myeloproliferative ****	****Syndrome: JMML**

## For Perspective-Adult MDS

**Predominant feature: Marrow Failure**
**Most frequent in adults 40-60 yrs. **
**Two major clinical groups****1. High incidence of progression to AML:****	****Multilineage/Mutator Phenotype****2. Low Progression to AML:****	****Unilineage**

## Types of Adult MDS

**High Incidence of progression to AML:****Refractory Cytopenia with multilineage dysplasia: (RCMD)****Refractory Anemia with excess Blasts (RAEB)**
**Low Incidence of progression to AML:****Refractory Anemia****Refractory anemia with ringed sideroblasts****del 5q: Macrocytic anemia**

## Pediatric MDS

**Often with an underlying condition:****Aplastic anemia, Fanconi anemia, platelet storage pool defect, neurofibromatosis, secondary to malignancy treatment ****Syndromes: Down, Kostmann’s, Shwachman-Diamond, Dyskeratosis congenita, Bloom’s, Noonan’s****Amegakaryocytic thrombocytopenia****Familial monosomy 7, 5q-**

## Differential Diagnoses of MDS:Need >1 Marrow Finding and Cytogenetic Data

**Other anemias:megaloblastic****	****	****	****congenital dyserythropoietic****	****	****	****sideroblastic anemia**
**Leukemia/pre-leukemia:Megakaryocytic leuk.****	****	****	****Myelofibrosis****	****	****	****PNH**
**Toxins: Arsenic, chemotherapy**
**Virus: HIV**

## Myelodysplastic Syndrome (MDS)

**Refractory cytopenia (RC): <2% PB blasts,****<5% marrow blasts**
**Refractory anemia with excess blasts (RAEB):****2-19% PB blasts, 5-19% marrow blasts**
****RAEB in transformation (RAEB-T) ******PB or marrow blasts 20-29%: Now = AML******(Change from Handout)***
**Marrow abnormalities: 2-3 lineages dysmorphic, erythroid most abnormal**

## Molecular Genetics of MDS

**AML1/RUNX1 gene: point mutations****Regulates hematopoiesis & most frequent translocation in MDS********AML**
**Chromosome 7 & 20 abnormalities in Shwachman synd: “mutator phenotype”**

## Treatment of MDS

**Refractory cytopenia: “expectant follow-up”**
**RAEB/RAEB-T:**
**	****	****	****	****   **_**Chemotherapy**_**	****  **_**BMT**_
**Event-free survival:****	****14-55%****	****  65-80%**
**  ****(If successful induction)**

## Down Syndrome Proliferative Diseases

**Transient abnormal myelopoiesis (TAM)**** **
**Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)**

## DOWN SYNDROMETransient Myeloproliferative Disorder orTransient Abnormal Myelopoiesis

**TMD/TAM: leukemoid reaction: usually megakaryocytic**
**Progression to megakaryocytic leukemia:20%****Blasts same in both by morphology, immuno-phenotype ****GATA-1 *exon 2 mutations in leukemia only****Ultimately clonal cytogenetic data differentiates**

## Transient Abnormal Myelopoiesis in Down Syndrome

**	****	****	****	****	**_**Median**_**	**_**Range**_
**Age at onset (days)****	****     2****	****	****  0-180**
**Hepatosplenomegaly****	****    69%**
**Bruising/petech/bleeding   25%**
**Resp. distress****	****	****    21%**
**WBC (per ********l)****	****	****47,000      5,000-384,000**
**Absolute blast ct.****	****	****13,000****	****0-280,000**
**Hgb (g/dl)****	****	****	****    16.8****	****   4-23.2**
**Platelets (per ********l) ****	****	****102,000    5,000-1,800,000**

## TAM Marrow Characteristics

**Hypo- to hypercellular**
**Fibrosis common**
**Blasts 32%  (range 6.8-80%)**
***Immunophenotype: CD7,33,45,34+****Platelet markers CD41/42b/61: variably +****Best is EM with immunogold labeling of CD61**

## TAMClinical Outcomes

**Onset: median 16 mo. (range 1-30 mo.)** **No clinical differences between those with or without ANLL**
**Duration: *Clear blasts median 2 mo., max 6 mo.**
***Leukemia 20% (9-38 mo.) 90% M7, rare ALL**
**17% died in first few mo. (not leukemia): ****sepsis, congestive heart failure, hyperviscosity, “crib death”, DIC**
**But....33% additional hematologic problems:****   84% of these developed ANLL**** Others: CML, MDS, chronic thrombocytopenia**

## Pediatric MDS Classification:Myelodysplastic/myeloproliferative

**Juvenile myelomonocytic leukemia****1% of pediatric leukemia cases**
**Chronic myelomonocytic leukemia*****Very uncommon in children***
***BCR/ABL-*****negative chronic myelogenous leukemia**

## Juvenile Myelomonocytic Leukemia JMML

**Clinical criteria: hepatosplenomegaly, lymphadenopathy, pallor, fever, skin rash**** **
**Minimal lab criteria (need all 3)****   No t9;22 or *****bcr/abl***** rearrangement****   Peripheral blood monocytosis: >1X10****9****/L**
**	****   ****Bone marrow blasts <20% (*****differs from handout)***
**	**

## JMMLAdditional Lab Criteria

**Need at least 2 of these:****-****Hgb F increased for age****-Myeloid precursors in periph. blood smear****-WBC >10****9****/L****-Clonal abnormality not always present         ****	****(monosomy 7, t(5;8), trisomy 8, monosomy 22)****-GM-CSF hypersensitivity of monocyte ****	****progenitors i*****n vitro******-*****Autonomous growth of CD34+ cells**

## Molecular Pathogenesis of JMML

**Frequent deletions of *****NF1*****Negative regulator of Ras signaling**
**Missense mutations in *****PTPN11: *****all Noonan synd. Pts with JMML and 35% of other JMML**
**Mutations of *****KRAS2 *****& *****NRAS***
**Bottom line: Ras activation central to JMML and other leukemias**

## MDS vs AML vs JMML

| DiagnosisMDS | Age
< 7 yr |  Spleen/liver      20-25% | Nodes    Rare |
| --- | --- | --- | --- |
| AML | > 7 yr |       >50% |    ~25% |
| JMML | 1.3 yr |      75-80% |      40% |

## MDS vs AML vs JMML

| Diagnosis

MDS | Extra-medul. Dx.  No | WBC~7,000/l | NormalCytogenet.23% |
| --- | --- | --- | --- |
| AML | Rare+ M4/M5 | >20,000/l
 | Rare |
| JMML | 77% | >25,000/l
 | 78% |

## Transformation to Leukemia:JMML/MDS/TMS

|  |     TIME     <2 | TO 2-5 | TRANSFORM (yr)            5-10 | Total |
| --- | --- | --- | --- | --- |
| JMML |       5/60 |  3 |  | 8/6013% |
| MDS |    33/101   | 6 |                2 | 41/10141% |
| TMS |     4/6 | 1 |        |   5/6 83% |
| Total |     42 | 10 |                 2 | 54/167 32% |

## Treatment of JMML

**Chemotherapy: 16% survival rate @ 3 yrs.****Median time diagnosis to death is 15 mo.**
**Stem cell transplant: 50% survival**
***Current COG trial: pre-transplant chemotherapy**_***cis***__**-Retinoic acid**_**: inhib “spontanteous outgrowth  CFU-GM**_**fludarabine**_**: potentiate metabolism of Ara-C to Ara-CTP**_**Ara-C:**_** potent anti-myeloid malignancy therapy**_**farnesyl protein transferase inhb:**_** anti-Ras*****= New data not in syllabus**

## What is a myeloproliferative disorder?

**Elevated numbers of a particular cell line in peripheral blood**
**Hyperplasia of that lineage in the marrow**
**No secondary causes: infection, drugs, toxins, autoimmune, non-hematologic malignancy, trauma**

## Types of Myeloproliferative Syndromes

**Erythroid: polycythemia vera**
**Granulocytic: CML**
**Monocytic: JMML**
**Megakaryocytic: Essential or familial thrombocytosis, myeloproliferative disease of Down syndrome**** **
**Gain of function mutation in Janus kinase 2 (9pLOH):polycythemia vera & familial thrombocytosis**

## Myeloproliferative DisordersPolycythemia Vera

**<1% before age 25 **
**Symptoms:headache, weakness, pruritus, dizziness, night sweats, weight loss**
**P.E.: hypertension, hepatosplenomegaly**
**Marrow: hypercellular**
**Erythropoietin normal or  min. decreased**
**10-25% have clonal abnormality**

## Polycythemia Vera:Criteria for diagnosis

**Need A1-3 or A1 &2 plus 2 of Category B**
**Category A:****1. RBC vol. Males >36ml/kg, females>32ml/kg**
**	****2. Arterial oxygen saturation >92% (normal P-50)**
**	****3. Splenomegaly**
**Category B:**
**	****1. Thrombocytosis (>400,000/********l)**
**	****2. Leucocytosis (12,000/ ********l)**
**	****3. Increased leukocyte alkaline phosphatase**
**	****4. Increased vit B12 (900 pg/ml) or unsat. B12 binding capacity (>2200 pg/ml)**

## Polycythemia Vera

**Treatment: phlebotomy, keep hct <45%**
**Problems: vascular occlusion, bleeding, thrombosis, myelofibrosis, leukemia**

## Essential Thrombocytosis

**After ruling out: ****nutritional, metabolic, infectious, traumatic, inflammatory, neoplastic, drug, and misc.**
**Platelet count > 600,000/********l**
**Hgb not > 13 gm/dl**
**Normal iron stores**
**No Ph. Chromosome**
**No fibrosis of marrow**

## Essential Thrombocythemia

**Presents with: headache, thrombosis (0-32%), bleeding (12-37%) (G.I.,hemoptysis) **
**Over 1⁄2 peds cases familial**
**Splenomegaly (30-60%)**
**Hepatomegaly (7-43%)**
**Abnl plt morphol: 75-85% ****(hyperlobulated, dysplastic, ******** early megs., **

## Essential Thrombocytosis:Therapy and late effects

**Safest therapy: anagrelide: anti-aggregating and decreased platelet synthesis****Others: hydroxyurea, **
**Malignant transformation:****0% Familial,    11% non-familial**
**Thrombosis can occur @ plt cts of 600-800K**

## Histiocytosis Syndromes

**Langerhans cell **
**Macrophage proliferations****Hemophagocytic lymphohistiocytosis****   ****Familial and “Secondary” to many etiologies****Macrophage activation syndrome****Rosai-Dorfman Syndrome**
**	****Juvenile Xanthogranuloma**
**Malignancies of macrophages or dendritic cells**** **

## Where do all those histiocytes come from?

**Stem Cell**

**Langerhans**
**     ****Cell****    ****LCH**

**Follicular**
**DC**

**Myeloid **
**DC****HLH/RD**

**Interstitial**
**DC****JXG/ECD**

**Common Myeloid Progenitor**

**Common lymphoid**
**Progenitor**

**Mono/preDC1**

**Monocyte**

**preDC2**

**Plasmcytoid**
**   ****DC**

***GM-CSF. IL-4***
***TGF-************, Flt-3L***

***TNF-************, GM-CSF***

***TGF-*********

## Langerhans cell histiocysosis

**Incidence: 5-8/million children**
**Male/female: 1.3/1**
**Average age at presentation: 2.4 yrs**
**Multisystem and single system disease****Severity depends on organs involved**
**Epidemiologic associations: increased incidence of thyroid/autoimmune disease in family**

## Langerhans Cell Characteristics

**Dendritic cells derived from bone marrow stem cells**
**Critical antigen-presenting cell**
**For correct diagnosis:****Intracellular Birbeck granules that stain with CD207 (Langerin) *****or *****Extracellular staining with CD1a**** **
**Also found, but not specific: S100+**

## Slide 38

## Slide 39

## Langerhans Cell Histiocytosis: Clinical manifestations I

**painful swelling of bones**
**unifocal bone lesion (31% at presentation)**
**isolated multifocal bone involvement (19%)**
**persistent otitis /  mastoiditis**
**mandible involvement (“floating teeth”) **
**Papular/scaly rash (37% at presentation)**
**hepatosplenomegaly **
**lymphadenopathy**

## Langerhans Cell Histiocytosis: Clinical manifestations II

**Pulmonary involvement : interstitial pattern -> “honeycombing” (cysts) and nodules**
**Marrow infiltration: cytopenias , sometimes    hemophagocytosis-macrophage activation**
**GI involvement (diarrhea, malabsorption)**
**Endocrine involvement:**
**diabetes insipidus**
**growth failure**
**hypothyroidism**

## Slide 42

## Originally thought to be a viral rash

## Slide 44

## Slide 45

## Slide 46

## Slide 47

## Pulmonary LCH in Children

**Presentation: wheezing, cough, pain,or nothing**
**Chest xray: interstitial infiltrates, sometimes see nodules, cysts, or pneumothorax**
**Chest CT needed to define presence of nodules and cysts. Probably reasonable to do on all infants**

## CNS PROBLEMS IN LCH PTS. WITH BASE OF SKULL LESIONS

**Mastoid, orbital, temporal bone lesions:**
**If single agent or no treatment: 40% incidence of diabetes insipidus**
**Velban/prednisone: still 20% D.I.**
**Chance of parenchymal brain disease: ****May present 10 yrs after initial diagnosis**

## Neurologic Syndromes in LCH

**Present with ataxia, dysarthria, dysmetria, behavior changes**
**MRI: Masses or T2 hyper-intense signal in cerebellar white matter, pons, or basal ganglia may be long before symptoms appear**
**Secondary to neurodegeneration/gliosis**
**Cause: Cytokines? Direct infiltration with Langerhans cells or lymphocytes?**

## Slide 51

## Enhanced T2-weighted images in LCH patient with neurodegenerative syndrome

## LCH Therapy

**“****Low Risk” (bone +/-skin,lymph nodes): ****velban/prednisone 6-12 mo.**
**“****High Risk” (liver, spleen, lung, bone marrow)****velban/prednisone/6MP  *****vs *****velban/prednisone/6MP/methotrexate****Both 12 mo.**
**Etoposide (VP-16) no better than velban, now not considered “standard therapy”**
**Radiotherapy or intra-lesion steroids only for spine, femur, or non-CNS Risk skull lesions**

## LCH Therapy Results

**“****Low Risk” pts: 100% cured****18-25% reactivations**
**“****High Risk” pts: Depends on response @  6wks**
**	****Good response: 6% fatalities****Intermediate:  21% fatalities**
**	****Non-responder: 60% fatalities**

## Hemophagocytic LymphohistiocytosisHLH

**Autosomal recessive and secondary forms****Both may be triggered by infections, malignancy, or immunizations**
**Presentation: fever, irritability, rash, lymphadenopathy, hepatosplenomegaly**
**Labs: pancytopenia, coagulopathy, elevated: LFTs, ferritin, triglyceride**
**Histology of marrow, nodes, or liver: macrophages actively engulfing any blood cell**

## HLH: Associated Conditions

**Familial, especially in cultures with consanguinity**
**Secondary to any infectious agent****Especially EBV, CMV, parvo**
**Malignancies: T and B cell leukemias, T-cell lymphoma, germ cell tumor**
**Kawasaki synd., JRA, lupus**
**Other syndromes: X-linked lymphoprolif., Griscelli, Chediak-Higashi**** **

## HLH Epidemiology

**Frequency: 1.2/million children or 1/50,000 live births. ****Compare PKU 1/31,000 or galactosemia 1/84,000**** **
**Likely under-diagnosed. “Looks like” hepatitis, sepsis, multi-organ failure syndromes**** **

## HLH: Clinical Signs

**Fever  91%**
**Hepatopmegaly  90%**
**Splenomegaly 84%**
**Neurologic symptoms 47%**
**Rash 43%**
**Lymphadenopathy 42%**

## CNS Problems in HLH

**Cranial nerve signs**
**Confusion, seizures, increased intracranial pressure**
**Brain stem symptoms, ataxia**
**Subdural effusions & bleeds, retinal hemorh.**
**CSF: mononuclear pleocytosis (lymphs & monos), RBC**
**MRI: parameningeal infiltrations, masses or necrosis- hypodense areas**

## Diagnostic Criteria for HLH

**Familial disease/known genetic defect**
**5 of the following :**
**Fever ****≥ 7 days**
**Splenomegaly**
**Cytopenia ****≥ 2 cell lines**
**Hypertriglyceridemia and/or hypofibrinogenemia**
**Ferritin ≥ 4000 ****μ****g/L**
**sCD25 ≥ 2,400 U/mL**
**Decreased or absent NK activity**
**Hemophagocytosis (Absent 20% of time-treatment may be indicated if other criteria fulfilled)**

**Notes:**
In 1991, the familial hemophagocytic lymphohistiocytosis study group of the histiocyte society proposed guidelines for HLH.

Hb < 9 (below 4 weeks < 10)
Plt < 100
ANC < 1000

hyperTG can rise during course of infections but apart from bacterial sepsis usually does not surpass values of 3mmol/l in children with fever. A German study shows that of 65 patients with HLH, 69% had TG over 3mmol/l and 35% over 5mmol/l.

Hypofibrinogenemia isa rather specific marker for HLH but is not sensitif, only 53% of patients had fibrinogen levels below 1.5g/l

Ferritin may be elevated in children with infection but would remain below 200ug/l apart from HIV infection. Acute hepatocyte lysis can give rise to ferritin, hepatocyte being the main source of ferritin of the body. Overall, sensitivity of this marker was 69% in the cohort of German patients. Of note also, newborn may have high values without infection, and patients with juvenile rheumatoid arthritis without any sign of MAS can have elevated ferritin up to the 10,000
The marker with the highest sensitivity, 93%, is a sCD25 value above 2400, but specificity is very low compared with sepsis, infection or leukemia and lymphomas.

Finally, NK cell activity quantification is an important diagnostic marker but is usually not available in time for treatment decision. 

The marrow has usually a normal cellularity and increased – but inefficient – erythropoiesis as demonstrated with by an inadequate reticulocyte count in the presence of anemia. Hemophagocytosis is revealed by an increased number of histiocytes engulfing red cells, erythroblasts, platelets and white cells. IN the German series, hemophagocytosis was present in only 32% of the cases in the first bone marrow and 85% at diagnosis.

A spinal tap is mandatory but not always possible at diagnosis due to coagulation disorders; findings in favor of HLH are moderate pleocytosis and/or elevated protein; of note, most patients are asymptomatic; MRI is also strongly recommended. 

Supportive evidence include cerebral symptoms with moderate pleiocytosis and/or elevated proteim, elevated transaminases, bilirubin, LDH>1000 U/mL

## FEVER OF UNKNOWN ORIGIN: EVALUATION MAY LEAD TO A SURPRISE

## Slide 62

## Immune Dysfunction in LCH

**Defective NK cell function (number variable) Decreased killing of target cells****Decreased perforin (usually)**
**Defective Cytotoxic T cells****Decreased perforin (usually), may differ from****NK cell findings**
**Effects of above: unregulated cytokine production, no apoptosis of lymphs and monos**

## Peforin Defects in HLH

**Peforin: cytolytic effector protein, essential for regulation of NK and T cells**
**Levels in NK and T cells depend on type of mutations in the gene.  May be normal in patients with MUNC-13 or other mutations**
**>50 mutations in the *****PRF1***** gene known: cause absence of functional protein or truncated proteins. No gross deletions or insertions.**

## Molecular Genetics of Familial HLH

| LocusName |   GeneSymbol | Chrmsm.  Locus | Protein  Name |
| --- | --- | --- | --- |
| FHL1 | Unknown |   9q21.3-q22 | Unknown |
| FHL2 | PRF1 | 10q22 | Peforin 1 |
| FHL3 | UNC13D | 17q25.1 | Unc-13 homolog D |
| FHL4 | STX11 | 6q24.1 | Syntaxin-11 |

## Hypercytokinemia in HLH

**Dysregulation of Th1 immunresponse********Markedly elevated levels of: Interferon ********,****TNF********, IL-1********, IL-6, IL-2 receptor (sCD-25)**
**Cause fever, hyperlipidemia, endothelial activation, tissue infiltration by lymphs & histiocytes, hepatic triaditis, CNS vasculitis, demyelination, marrow hyperplasia or aplasia**

## HLH-94 RESULTS

**113 Patients, 1994-1998, < 15 yrs of age**
**25 familial, 88 sporadic**
**Overall survival 55% ****+/-9%,**** 51% for familial cases****BMT need for familial or genetically proven patients**
**23/113 alive with only immunochemotherapy **
**	**** ****VP-16/dexamethasone/cyclosporine **
**78% of children respond well to immunochemother.**
**93 bone marrow transplants****62% survival (52% for <3mo to 71% for 12-24 mo)**

## One More---

**	****Rosai Dorfman Syndrome   *****OR*****Sinus Histiocytosis with Massive ****	****	****Lymphadenopathy**

## Slide 69

## Anatomic Sites of SHML

_**Site**__	_				_**Frequency (%)**_
**Lymph nodes****	****	****	****	****87**
**Skin and soft tissue****	****	****	****16**
**Nasal cavity****	****	****	****	****16**
**Eye****	****	****	****	****	****	****11**
**Bone****	****	****	****	****	****	****11**
**Central Nervous System****	****	**** 7**
**Salivary gland****	****	****	**** ****	**** 7**
**Kidney****	****	****	****	**** ****	**** 3*******
**Respiratory tract****	****	**** ****	****	**** 3*******
**Liver****	****	****	****	****	****	**** 1*******
**Breast, GI, Heart****	****	****	****	****<1**
**	****	****	**

**Notes:**
What is missing from this list is the SPLEEN
Splenomegaly is extremely rare in contrast to frequent splenic involvement in hematolymphoid and other histiocytic/dendritic cell disorders

## “Activated histiocyte”
Pan macrophage
Lysosomal
Activation
S100
CD163
Lacks CD1a

- Immunohistochemistry

**CD163**

**S100**

- “Activated histiocyte”
- Pan macrophage
- Lysosomal
- Activation
- S100
- CD163
- Lacks CD1a

**Notes:**
Pan macrophage antigens: CD68, HAM56, CD14, CD64, CD15
Markers of lysosomal activity
Markers of “activation” (IL2R/CD25, CD30?)
Markers of cells derived from monocytes (rather than tissue macrophages); “activated histiocytes”

## Differential Diagnosis

**Reactive hyperplasia**
**Hemato-lymphoid malignancy**
**Metastasis**
**Storage disorders**
**Histiocytoses, particularly, LCH**

**Notes:**
Reactive
Inflammatory
Infectious (EBV-associated/infectious mononucleosis)
Granulomatous/necrotizing lymphadenitis
Hematolymphoid
Hodgkin and non-Hodgkin lymphoma
Acute leukemia, especially lymphoblastic leukemia & monocytic leukemia
Metastasis
Carcinoma
Sarcoma
Germ cell tumors ( especially in children)
Storage disorders 
Such as Gauchers with proliferation of foamy histiocytes
Histiocytoses
Reactive histiocytosis including hemophagocytic lymphohistiocytosis
Malignant tumors of histiocytes and accessory dendritic cells
Langerhans cell histiocytosis

Examples are chosen to highlight reactive, metastatic and histiocytic (LCH) disorders.

## TreatmentThoughts from the Registry

**Randomized clinical trials unavailable**
**Most patients do not require treatment?**
**Treatment necessary in minority with organ or life-threatening complications**

**Notes:**
Information on treatment is bases on retrospective study of registry patients, many of whom have incomplete data [Komp et al, Sem Diag Pathol 1990]
Case reports and small series in the literature
Objective measures of clinical response are lacking

## Chemotherapy

**Vinca alkaloids/alkylating agents/steroids**
**Methotrexate + 6-mercaptopurine (2/2CR)**
**Purine analog 2-chlorodeoxyadenosine used in refractory LCH**
**Short-term symptomatic relief in 2 children with CNS disease without clinical response**

***Rodriguez-Galindo J Pediatr Hematol Oncol 2004***