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
• 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, ShwachmanDiamond, 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, immunophenotype
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: >1X109/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 >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
 Spleen/liver Nodes
20-25%
Rare
Diagnosis
MDS
Age
< 7 yr
AML
> 7 yr
>50%
~25%
JMML
1.3 yr
75-80%
40%
MDS vs AML vs JMML
Diagnosis Extra-medul. WBC
Dx.
No
~7,000/l
MDS
Normal
Cytogenet.
23%
AML
Rare
+ M4/M5
>20,000/l Rare
JMML
77%
>25,000/l 78%
Transformation to Leukemia:
JMML/MDS/TMS
JMML
TIME
<2
5/60
TO TRANSFORM (yr)
2-5
5-10
Total
3
8/60
13%
41/101
41%
5/6
83%
54/167
32%
MDS
33/101
6
TMS
4/6
1
Total
42
10
2
2
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 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
from?
Stem Cell
Common
Myeloid
Progenitor
Common
lymphoid
Progenitor
TNF-, GM-CSF
Mono/preDC1
Monocyte
TGF-
Langerhans
Cell
LCH
preDC2
GM-CSF. IL-4
TGF-, Flt-3L
Interstitial
DC
JXG/ECD
Follicular
DC
Myeloid
DC
HLH/RD
Plasmcytoid
DC
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+
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
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?
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 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)
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
• 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
FHL1
Unknown
FHL2
PRF1
10q22
Peforin 1
FHL3
UNC13D
17q25.1
Unc-13
homolog D
FHL4
STX11
6q24.1
Syntaxin-11
9q21.3-q22
Protein
Name
Unknown
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
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
Immunohistochemistry
S100
• “Activated histiocyte”
– Pan macrophage
– Lysosomal
– Activation
• S100
• CD163
• Lacks CD1a
CD163
Differential Diagnosis
• Reactive hyperplasia
• Hemato-lymphoid malignancy
• Metastasis
• Storage disorders
• Histiocytoses, particularly, LCH
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
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