Transcript Myeloproliferative, Myelodysplastic, and Histiocytic Disorders
Myelodysplastic, Myeloproliferative, and Histiocytic Disorders
Kenneth McClain M.D. Ph.D.
Texas Children’s Cancer Center Houston, TX
Disclosure Information
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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?
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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
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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
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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
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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
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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
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Other anemias:megaloblastic congenital dyserythropoietic sideroblastic anemia Leukemia/pre-leukemia:Megakaryocytic leuk.
Myelofibrosis PNH Toxins: Arsenic, chemotherapy Virus: HIV
Myelodysplastic Syndrome (MDS)
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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
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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
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Refractory cytopenia: “expectant follow-up” RAEB/RAEB-T: Chemotherapy BMT Event-free survival: 14-55% 65-80% (If successful induction)
Down Syndrome Proliferative Diseases
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Transient abnormal myelopoiesis (TAM)
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Myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
DOWN SYNDROME Transient Myeloproliferative Disorder or Transient Abnormal Myelopoiesis
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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) Hepatosplenomegaly 2 69% 0-180 Bruising/petech/bleeding 25% Resp. distress WBC (per
l) 21% 47,000 5,000-384,000 Absolute blast ct.
Hgb (g/dl) Platelets (per
l) 13,000 16.8
0-280,000 4-23.2
102,000 5,000-1,800,000
TAM Marrow Characteristics
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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
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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
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Juvenile myelomonocytic leukemia 1% of pediatric leukemia cases Chronic myelomonocytic leukemia
Very uncommon in children
BCR/ABL-negative chronic myelogenous leukemia
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Juvenile Myelomonocytic Leukemia JMML
Clinical criteria: hepatosplenomegaly, lymphadenopathy, pallor, fever, skin rash
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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 in vitro -Autonomous growth of CD34+ cells
Molecular Pathogenesis of JMML
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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 AML > 7 yr
Spleen/liver 20-25%
Nodes Rare >50% ~25% JMML 1.3 yr 75-80% 40%
MDS vs AML vs JMML
Diagnosis Extra-medul. Dx.
No MDS AML Rare + M4/M5 WBC ~7,000/
l Normal Cytogenet.
23% >20,000/
l Rare JMML 77% >25,000/
l 78%
Transformation to Leukemia: JMML/MDS/TMS
JMML MDS TMS Total TIME <2 5/60 TO 2-5 TRANSFORM (yr) 5-10 3 33/101 4/6 42 6 1 10 2 2 Total 8/60 13% 41/101 41% 5/6 83% 54/167 32%
Treatment of JMML
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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?
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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
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Erythroid: polycythemia vera Granulocytic: CML Monocytic: JMML Megakaryocytic: Essential or familial thrombocytosis, myeloproliferative disease of Down syndrome
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Gain of function mutation in Janus kinase 2 (9pLOH):polycythemia vera & familial thrombocytosis
Myeloproliferative Disorders Polycythemia Vera
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<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
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Treatment: phlebotomy, keep hct <45% Problems: vascular occlusion, bleeding, thrombosis, myelofibrosis, leukemia
Essential Thrombocytosis
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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
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Presents with: headache, thrombosis (0-32%), bleeding (12-37%) (G.I.,hemoptysis) Over ½ peds cases familial Splenomegaly (30-60%) Hepatomegaly (7-43%) Abnl plt morphol: 75-85% (hyperlobulated, dysplastic,
early megs.,
Essential Thrombocytosis: Therapy and late effects
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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
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Langerhans cell Macrophage proliferations Hemophagocytic lymphohistiocytosis Familial and “Secondary” to many etiologies Macrophage activation syndrome Rosai-Dorfman Syndrome Juvenile Xanthogranuloma
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Malignancies of macrophages or dendritic cells
Where do all those histiocytes come from?
Stem Cell Common Myeloid Progenitor
TNF-
, GM-CSF
Common lymphoid Progenitor
TGF-
Mono/preDC1 Monocyte
GM-CSF. IL-4 TGF-
, Flt-3L
preDC2 Langerhans Cell LCH Interstitial DC JXG/ECD Follicular DC Myeloid DC HLH/RD Plasmcytoid DC
Langerhans cell histiocysosis
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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
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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
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Also found, but not specific: S100+
Langerhans Cell Histiocytosis: Clinical manifestations I
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painful swelling of bones
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unifocal bone lesion (31% at presentation)
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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
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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
Originally thought to be a viral rash
Pulmonary LCH in Children
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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
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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
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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?
Enhanced T2-weighted images in LCH patient with neurodegenerative syndrome
LCH Therapy
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“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
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“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
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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
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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
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Frequency: 1.2/million children or 1/50,000 live births. Compare PKU 1/31,000 or galactosemia 1/84,000
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Likely under-diagnosed. “Looks like” hepatitis, sepsis, multi-organ failure syndromes
HLH: Clinical Signs
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Fever 91% Hepatopmegaly 90% Splenomegaly 84% Neurologic symptoms 47% Rash 43% Lymphadenopathy 42%
CNS Problems in HLH
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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
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Familial disease/known genetic defect 5 of the following :
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Fever ≥ 7 days
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Splenomegaly
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Cytopenia ≥ 2 cell lines
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Hypertriglyceridemia and/or hypofibrinogenemia
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Ferritin ≥ 4000 μg/L
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sCD25 ≥ 2,400 U/mL
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Decreased or absent NK activity
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Hemophagocytosis (Absent 20% of time-treatment may be indicated if other criteria fulfilled)
FEVER OF UNKNOWN ORIGIN: EVALUATION MAY LEAD TO A SURPRISE
CLINICAL FINDINGS Fever Hypotension Respiratory distress LAB FINDINGS CBC Abnl LFTs/Bili up LDH Increased OTHER LABS PT/PTT up Fibrinogen down FERRITIN: WAY UP!!
ORDER Infectious agents tests HEME CONSULT Bone marrow asp.
START HLH Rx IF: BMA + BMA- & clinical criteria strong
Immune Dysfunction in LCH
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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
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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 FHL1 FHL2 FHL3 FHL4 Gene Symbol Unknown
PRF1 UNC13D STX11
Chrmsm.
Locus 9q21.3-q22 Protein Name Unknown 10q22 17q25.1
6q24.1
Peforin 1 Unc-13 homolog D Syntaxin-11
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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
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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
Anatomic Sites of SHML
Site Lymph nodes Skin and soft tissue Nasal cavity Eye Bone Central Nervous System Salivary gland Kidney Respiratory tract Liver Breast, GI, Heart Frequency (%) 87 16 16 11 11 7 7 3 * 3 * 1 * <1
S100
Immunohistochemistry
• “Activated histiocyte” – Pan macrophage – Lysosomal – Activation • S100 • CD163 • Lacks CD1a
CD163
Differential Diagnosis
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Reactive hyperplasia
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Hemato-lymphoid malignancy
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Metastasis
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Storage disorders
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Histiocytoses, particularly, LCH
Treatment
Thoughts from the Registry
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Randomized clinical trials unavailable
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Most patients do not require treatment?
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Treatment necessary in minority with organ or life-threatening complications
Chemotherapy
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Vinca alkaloids/alkylating agents/steroids
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Methotrexate + 6-mercaptopurine (2/2CR)
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Purine analog 2-chlorodeoxyadenosine used in refractory LCH
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Short-term symptomatic relief in 2 children with CNS disease without clinical response
Rodriguez-Galindo J Pediatr Hematol Oncol 2004