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Myelodysplastic, Myeloproliferative, and Histiocytic Disorders

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Title: Myelodysplastic, Myeloproliferative, and Histiocytic Disorders


1
Myelodysplastic, Myeloproliferative, and
Histiocytic Disorders
  • Kenneth McClain M.D. Ph.D.
  • Texas Childrens Cancer Center
  • Houston, TX

2
Disclosure Information
  • Own common stock of Johnson Johnson Co.
  • No discussion of unlabeled usesNew material
    not in syllabus

3
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)

4
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

5
Pediatric MDS Classification
  • Three major categories1. Adult-Type
    Myelodysplastic Syndromes2. Down Syndrome with
    abnormal megakaryocyte proliferation3.
    Myelodysplastic/Myeloproliferative Syndrome JMML

6
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

7
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

8
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-

9
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

10
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

11
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

12
Treatment of MDS
  • Refractory cytopenia expectant follow-up
  • RAEB/RAEB-T
  • Chemotherapy BMT
  • Event-free survival 14-55 65-80
  • (If successful induction)

13
Down Syndrome Proliferative Diseases
  • Transient abnormal myelopoiesis (TAM)
  • Myelodysplastic syndrome (MDS)/acute myeloid
    leukemia (AML)

14
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

15
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

16
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

17
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

18
Pediatric MDS ClassificationMyelodysplastic/myel
oproliferative
  • Juvenile myelomonocytic leukemia1 of pediatric
    leukemia cases
  • Chronic myelomonocytic leukemiaVery uncommon in
    children
  • BCR/ABL-negative chronic myelogenous leukemia

19
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)

20
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

21
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

22
MDS vs AML vs JMML
23
MDS vs AML vs JMML
24
Transformation to LeukemiaJMML/MDS/TMS
25
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

26
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

27
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

28
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

29
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)

30
Polycythemia Vera
  • Treatment phlebotomy, keep hct
  • Problems vascular occlusion, bleeding,
    thrombosis, myelofibrosis, leukemia

31
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

32
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.,

33
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

34
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

35
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
36
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

37
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

38
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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

41
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

42
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43
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

49
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

50
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?

51
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52
Enhanced T2-weighted images in LCH patient with
neurodegenerative syndrome
53
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

54
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

55
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

56
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

57
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

58
HLH Clinical Signs
  • Fever 91
  • Hepatopmegaly 90
  • Splenomegaly 84
  • Neurologic symptoms 47
  • Rash 43
  • Lymphadenopathy 42

59
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

60
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)

61
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

64
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.

65
Molecular Genetics of Familial HLH
66
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

67
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

68
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
71
Immunohistochemistry
S100
  • Activated histiocyte
  • Pan macrophage
  • Lysosomal
  • Activation
  • S100
  • CD163
  • Lacks CD1a

CD163
72
Differential Diagnosis
  • Reactive hyperplasia
  • Hemato-lymphoid malignancy
  • Metastasis
  • Storage disorders
  • Histiocytoses, particularly, LCH

73
TreatmentThoughts from the Registry
  • Randomized clinical trials unavailable
  • Most patients do not require treatment?
  • Treatment necessary in minority with organ or
    life-threatening complications

74
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
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