Myeloproliferative Myelodysplastic and Histiocytic Disorders

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Myeloproliferative Myelodysplastic and Histiocytic Disorders Powered By Docstoc
					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 =
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:
          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,

  Amegakaryocytic thrombocytopenia
  Familial monosomy 7, 5q-
     Differential Diagnoses of MDS:
Need >1 Marrow Finding and Cytogenetic

• Other anemias:megaloblastic
                 congenital dyserythropoietic
                 sideroblastic anemia
• Leukemia/pre-leukemia:Megakaryocytic leuk.
• 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”
                    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
• Progression to megakaryocytic leukemia:20%
  Blasts same in both by morphology, immuno-
  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
              Clinical Outcomes
• Onset: median 16 mo. (range 1-30 mo.)
  No clinical differences between those with or without
• 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:
• Juvenile myelomonocytic leukemia
  1% of pediatric leukemia cases
• Chronic myelomonocytic leukemia
  Very uncommon in children
• BCR/ABL-negative chronic myelogenous
 Juvenile Myelomonocytic Leukemia
• Clinical criteria: hepatosplenomegaly,
  lymphadenopathy, pallor, fever, skin rash

• Minimal lab criteria (need all 3)
   No t9;22 or bcr/abl rearrangement

   Peripheral blood monocytosis: >1X109/L

   Bone marrow blasts <20% (differs from
          Additional 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(5;8), trisomy 8, monosomy 22)
  -GM-CSF hypersensitivity of monocyte
      progenitors in 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   Age       Spleen/liver Nodes
MDS         < 7 yr      20-25%       Rare

AML         > 7 yr      >50%        ~25%

JMML        1.3 yr     75-80%        40%
        MDS vs AML vs JMML

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

JMML     77%           >25,000/l 78%
        Transformation to Leukemia:

           TIME     TO TRANSFORM (yr)   Total
           <2       2-5    5-10
JMML        5/60    3                   8/60
MDS        33/101   6        2          41/101
TMS        4/6      1                    5/6
Total      42       10        2         54/167
               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,
          Types of Myeloproliferative
•   Erythroid: polycythemia vera
•   Granulocytic: CML
•   Monocytic: JMML
•   Megakaryocytic: Essential or familial
    thrombocytosis, myeloproliferative disease of Down

• Gain of function mutation in Janus kinase 2
  (9pLOH):polycythemia vera & familial
       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 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
• 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
                                Stem Cell
Common        TNF-, GM-CSF                                    lymphoid
Myeloid                                                        Progenitor
   TGF-                     GM-CSF. IL-4
                             TGF-, Flt-3L

 Langerhans   Interstitial       Follicular      Myeloid    Plasmcytoid
   Cell       DC                 DC              DC           DC
   LCH        JXG/ECD                            HLH/RD
      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
• 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+
     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
Originally thought to be a viral rash
      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
•    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?
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
  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
• 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
• 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
  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
• 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 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)
                    CLINICAL FINDINGS
                     Respiratory distress

      LAB FINDINGS                     OTHER LABS
        CBC Abnl                         PT/PTT up
       LFTs/Bili up                   Fibrinogen down
      LDH Increased                 FERRITIN: WAY UP!!

           ORDER                     HEME CONSULT
   Infectious agents tests           Bone marrow asp.

                                     START HLH Rx
                                           BMA +
                                BMA- & clinical criteria strong
     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     Gene     Chrmsm.       Protein
Name     Symbol     Locus         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
• 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
    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
• “Activated histiocyte”
  – Pan macrophage
  – Lysosomal
  – Activation             CD163
• S100
• CD163
• Lacks CD1a
   Differential Diagnosis
• Reactive hyperplasia
• Hemato-lymphoid malignancy
• Metastasis
• Storage disorders
• Histiocytoses, particularly, LCH
          Thoughts from the Registry
• Randomized clinical trials unavailable

• Most patients do not require treatment?

• Treatment necessary in minority with organ

 or life-threatening complications

• 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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