Myelodysplastic, Myeloproliferative, and Histiocytic Disorders

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Myelodysplastic, Myeloproliferative, and
Histiocytic Disorders

• Kenneth McClain M.D. Ph.D.
• Texas Childrens Cancer Center
• Houston, TX

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Disclosure Information

• Own common stock of Johnson Johnson Co.
• No discussion of unlabeled usesNew material
  not in syllabus
  

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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 followingSustained
  cytopeniaDysplasia in 2 cell linesClonal
  cytognenetic abnormality (5q-, monosomy 7)5-19
  Blasts (20 Blasts AML)

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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 million10-20 become
  AML

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Pediatric MDS Classification

• Three major categories1. Adult-Type
  Myelodysplastic Syndromes2. Down Syndrome with
  abnormal megakaryocyte proliferation3.
  Myelodysplastic/Myeloproliferative Syndrome JMML

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For Perspective-Adult MDS

• Predominant feature Marrow Failure
• Most frequent in adults 40-60 yrs.
• Two major clinical groups1. High incidence of
  progression to AML Multilineage/Mutator
  Phenotype2. Low Progression to AML Unilineage

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Types of Adult MDS

• High Incidence of progression to AMLRefractory
  Cytopenia with multilineage dysplasia
  (RCMD)Refractory Anemia with excess Blasts
  (RAEB)
• Low Incidence of progression to AMLRefractory
  AnemiaRefractory anemia with ringed
  sideroblastsdel 5q Macrocytic anemia
  

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Pediatric MDS

• Often with an underlying conditionAplastic
  anemia, Fanconi anemia, platelet storage pool
  defect, neurofibromatosis, secondary to
  malignancy treatment Syndromes Down,
  Kostmanns, Shwachman-Diamond, Dyskeratosis
  congenita, Blooms, NoonansAmegakaryocytic
  thrombocytopeniaFamilial monosomy 7, 5q-

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Differential Diagnoses of MDSNeed 1 Marrow
Finding and Cytogenetic Data

• Other anemiasmegaloblastic congenital
  dyserythropoietic sideroblastic anemia
  
• Leukemia/pre-leukemiaMegakaryocytic
  leuk. Myelofibrosis PNH
  
• Toxins Arsenic, chemotherapy
• Virus HIV

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Myelodysplastic Syndrome (MDS)

• Refractory cytopenia (RC) 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

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Molecular Genetics of MDS

• AML1/RUNX1 gene point mutationsRegulates
  hematopoiesis most frequent translocation in
  MDS?AML
  
• Chromosome 7 20 abnormalities in Shwachman
  synd mutator phenotype
  

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Treatment of MDS

• Refractory cytopenia expectant follow-up
• RAEB/RAEB-T
• Chemotherapy BMT
• Event-free survival 14-55 65-80
• (If successful induction)

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Down Syndrome Proliferative Diseases

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

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DOWN SYNDROMETransient Myeloproliferative
Disorder orTransient Abnormal Myelopoiesis

• TMD/TAM leukemoid reaction usually
  megakaryocytic
  
• Progression to megakaryocytic leukemia20Blasts
  same in both by morphology, immuno-phenotype
  GATA-1 exon 2 mutations in leukemia
  onlyUltimately clonal cytogenetic data
  differentiates

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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

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TAM Marrow Characteristics

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

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TAMClinical 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
  

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Pediatric MDS ClassificationMyelodysplastic/myel
oproliferative

• Juvenile myelomonocytic leukemia1 of pediatric
  leukemia cases
  
• Chronic myelomonocytic leukemiaVery 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
  
• Minimal lab criteria (need all 3) No t922 or
  bcr/abl rearrangement Peripheral blood
  monocytosis 1X109/L
  
• Bone marrow blasts handout)
  

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JMMLAdditional Lab Criteria

• Need at least 2 of these-Hgb F increased for
  age-Myeloid precursors in periph. blood
  smear-WBC 109/L-Clonal abnormality not always
  present (monosomy 7, t(58), trisomy 8,
  monosomy 22)-GM-CSF hypersensitivity of monocyte
  progenitors in vitro-Autonomous growth of CD34
  cells

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Molecular Pathogenesis of JMML

• Frequent deletions of NF1Negative 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

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MDS vs AML vs JMML
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MDS vs AML vs JMML
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Transformation to LeukemiaJMML/MDS/TMS
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Treatment of JMML

• Chemotherapy 16 survival rate _at_ 3 yrs.Median
  time diagnosis to death is 15 mo.
  
• Stem cell transplant 50 survival
• Current COG trial pre-transplant
  chemotherapycis-Retinoic acid inhib
  spontanteous outgrowth CFU-GMfludarabine
  potentiate metabolism of Ara-C to Ara-CTPAra-C
  potent anti-myeloid malignancy therapyfarnesyl
  protein transferase inhb anti-Ras New data
  not in syllabus

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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
  

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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
  

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Myeloproliferative DisordersPolycythemia Vera

• Symptomsheadache, weakness, pruritus, dizziness,
  night sweats, weight loss
  
• P.E. hypertension, hepatosplenomegaly
• Marrow hypercellular
• Erythropoietin normal or min. decreased
• 10-25 have clonal abnormality

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Polycythemia VeraCriteria for diagnosis

• Need A1-3 or A1 2 plus 2 of Category B
• Category A1. RBC vol. Males 36ml/kg,
  females32ml/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)

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Polycythemia Vera

• Treatment phlebotomy, keep hct
• Problems vascular occlusion, bleeding,
  thrombosis, myelofibrosis, leukemia

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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

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Essential Thrombocythemia

• 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.,
  

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Essential ThrombocytosisTherapy and late effects

• Safest therapy anagrelide anti-aggregating and
  decreased platelet synthesisOthers hydroxyurea,
  
  
• Malignant transformation0 Familial, 11
  non-familial
  
• Thrombosis can occur _at_ plt cts of 600-800K

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Histiocytosis Syndromes

• Langerhans cell
• Macrophage proliferationsHemophagocytic
  lymphohistiocytosis Familial and Secondary
  to many etiologiesMacrophage activation
  syndromeRosai-Dorfman Syndrome
• Juvenile Xanthogranuloma
• Malignancies of macrophages or dendritic cells

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Where do all those histiocytes come from?
Stem Cell
Common lymphoid Progenitor
Common Myeloid Progenitor
TNF-?, GM-CSF
Mono/preDC1
preDC2
Monocyte
GM-CSF. IL-4 TGF-?, Flt-3L
TGF-?
Langerhans Cell LCH
Follicular DC
Myeloid DCHLH/RD
Plasmcytoid DC
Interstitial DCJXG/ECD
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Langerhans cell histiocysosis

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

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Langerhans Cell Characteristics

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

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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

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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

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Originally thought to be a viral rash
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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

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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

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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?

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Enhanced T2-weighted images in LCH patient with
neurodegenerative syndrome
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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/methotrexateBoth 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

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LCH Therapy Results

• Low Risk pts 100 cured18-25 reactivations
• High Risk pts Depends on response _at_ 6wks
• Good response 6 fatalitiesIntermediate 21
  fatalities
  
• Non-responder 60 fatalities

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Hemophagocytic LymphohistiocytosisHLH

• Autosomal recessive and secondary formsBoth 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

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HLH Associated Conditions

• Familial, especially in cultures with
  consanguinity
  
• Secondary to any infectious agentEspecially 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

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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
  

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HLH Clinical Signs

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

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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
  

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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 µg/L
• sCD25 2,400 U/mL
• Decreased or absent NK activity
• Hemophagocytosis (Absent 20 of time-treatment
  may be indicated if other criteria fulfilled)

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FEVER OF UNKNOWN ORIGIN EVALUATION MAY LEAD TO A
SURPRISE
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Immune Dysfunction in LCH

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

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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.
  

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Molecular Genetics of Familial HLH
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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

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HLH-94 RESULTS

• 113 Patients, 1994-1998,
• 25 familial, 88 sporadic
• Overall survival 55 /-9, 51 for familial
  casesBMT 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 transplants62 survival (52 for
  

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One More---

• Rosai Dorfman Syndrome ORSinus Histiocytosis
  with Massive Lymphadenopathy

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Anatomic Sites of SHML
Site Frequency () Lymph nodes 87 Skin an
d soft tissue 16 Nasal cavity 16 Eye 1
1 Bone 11 Central Nervous System 7 Saliv
ary gland 7 Kidney 3 Respiratory tra
ct 3 Liver 1 Breast, GI, Heart 1
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Immunohistochemistry
S100

• Activated histiocyte
• Pan macrophage
• Lysosomal
• Activation
• S100
• CD163
• Lacks CD1a

CD163
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Differential Diagnosis

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

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TreatmentThoughts from the Registry

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

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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