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Myelodysplastic, Myeloproliferative, and Histiocytic Disorders

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1 Myelodysplastic, Myeloproliferative, and Histiocytic Disorders
Kenneth McClain M.D. Ph.D. Texas Children’s Cancer Center Houston, TX

2 Disclosure Information
Own common stock of Johnson & Johnson Co. No discussion of unlabeled uses *=New 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 following: Sustained cytopenia Dysplasia in 2 cell lines Clonal 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 million 10-20% become AML

5 Pediatric MDS Classification
Three major categories: 1. Adult-Type Myelodysplastic Syndromes 2. Down Syndrome with abnormal megakaryocyte proliferation 3. Myelodysplastic/Myeloproliferative Syndrome: JMML

6 For Perspective-Adult MDS
Predominant feature: Marrow Failure Most frequent in adults yrs. Two major clinical groups 1. High incidence of progression to AML: Multilineage/Mutator Phenotype 2. Low Progression to AML: Unilineage

7 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

8 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, Noonan’s Amegakaryocytic thrombocytopenia Familial monosomy 7, 5q-

9 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

10 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

11 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”

12 Treatment of MDS Refractory cytopenia: “expectant follow-up”
RAEB/RAEB-T: Chemotherapy BMT Event-free survival: 14-55% % (If successful induction)

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

14 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, immuno-phenotype GATA-1 *exon 2 mutations in leukemia only Ultimately clonal cytogenetic data differentiates

15 Transient Abnormal Myelopoiesis in Down Syndrome
Median Range Age at onset (days) Hepatosplenomegaly % Bruising/petech/bleeding 25% Resp. distress % WBC (per l) 47, , ,000 Absolute blast ct. 13, ,000 Hgb (g/dl) Platelets (per l) 102, ,000-1,800,000

16 TAM Marrow Characteristics
Hypo- to hypercellular Fibrosis common Blasts 32% (range %) *Immunophenotype: CD7,33,45,34+ Platelet markers CD41/42b/61: variably + Best is EM with immunogold labeling of CD61

17 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

18 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

19 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)

20 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

21 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

22 MDS vs AML vs JMML Diagnosis MDS Age < 7 yr  Spleen/liver 20-25%
Nodes Rare AML > 7 yr >50% ~25% JMML 1.3 yr 75-80% 40%

23 MDS vs AML vs JMML Diagnosis MDS Extra-medul. Dx. No WBC ~7,000/l
Normal Cytogenet.23% AML Rare + M4/M5 >20,000/l Rare JMML 77% >25,000/l 78%

24 Transformation to Leukemia: JMML/MDS/TMS
TIME <2 TO 2-5 TRANSFORM (yr) Total JMML 5/60 3 8/60 13% MDS 33/101 6 2 41/101 41% TMS 4/6 1 5/6 83% 42 10 54/ %

25 Treatment of JMML Chemotherapy: 16% survival 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

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 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

29 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)

30 Polycythemia Vera Treatment: phlebotomy, keep hct <45%
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 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 plt cts of K

34 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

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

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 disease Severity 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 diagnosis: Intracellular Birbeck granules that stain with CD207 (Langerin) or Extracellular staining with CD1a Also found, but not specific: S100+



40 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


43 Originally thought to be a viral rash





48 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

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?


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/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

54 LCH Therapy Results “Low Risk” pts: 100% cured 18-25% reactivations
“High Risk” pts: Depends on 6wks Good response: 6% fatalities Intermediate: 21% fatalities Non-responder: 60% fatalities

55 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

56 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

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) In 1991, the familial hemophagocytic lymphohistiocytosis study group of the histiocyte society proposed guidelines for HLH. Hb < 9 (below 4 weeks < 10) Plt < 100 ANC < 1000 hyperTG can rise during course of infections but apart from bacterial sepsis usually does not surpass values of 3mmol/l in children with fever. A German study shows that of 65 patients with HLH, 69% had TG over 3mmol/l and 35% over 5mmol/l. Hypofibrinogenemia isa rather specific marker for HLH but is not sensitif, only 53% of patients had fibrinogen levels below 1.5g/l Ferritin may be elevated in children with infection but would remain below 200ug/l apart from HIV infection. Acute hepatocyte lysis can give rise to ferritin, hepatocyte being the main source of ferritin of the body. Overall, sensitivity of this marker was 69% in the cohort of German patients. Of note also, newborn may have high values without infection, and patients with juvenile rheumatoid arthritis without any sign of MAS can have elevated ferritin up to the 10,000 The marker with the highest sensitivity, 93%, is a sCD25 value above 2400, but specificity is very low compared with sepsis, infection or leukemia and lymphomas. Finally, NK cell activity quantification is an important diagnostic marker but is usually not available in time for treatment decision. The marrow has usually a normal cellularity and increased – but inefficient – erythropoiesis as demonstrated with by an inadequate reticulocyte count in the presence of anemia. Hemophagocytosis is revealed by an increased number of histiocytes engulfing red cells, erythroblasts, platelets and white cells. IN the German series, hemophagocytosis was present in only 32% of the cases in the first bone marrow and 85% at diagnosis. A spinal tap is mandatory but not always possible at diagnosis due to coagulation disorders; findings in favor of HLH are moderate pleocytosis and/or elevated protein; of note, most patients are asymptomatic; MRI is also strongly recommended. Supportive evidence include cerebral symptoms with moderate pleiocytosis and/or elevated proteim, elevated transaminases, bilirubin, LDH>1000 U/mL



63 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

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
Locus Name Gene Symbol Chrmsm. Locus Protein Name FHL1 Unknown 9q21.3-q22 FHL2 PRF1 10q22 Peforin 1 FHL3 UNC13D 17q25.1 Unc-13 homolog D FHL4 STX11 6q24.1 Syntaxin-11

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, < 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 mo)

68 One More--- Rosai Dorfman Syndrome OR Sinus Histiocytosis with Massive Lymphadenopathy


70 Anatomic Sites of SHML Site Frequency (%) Lymph nodes 87
Skin and soft tissue 16 Nasal cavity 16 Eye Bone Central Nervous System 7 Salivary gland Kidney * Respiratory tract * Liver * Breast, GI, Heart <1 What is missing from this list is the SPLEEN Splenomegaly is extremely rare in contrast to frequent splenic involvement in hematolymphoid and other histiocytic/dendritic cell disorders

71 Immunohistochemistry
“Activated histiocyte” Pan macrophage Lysosomal Activation S100 CD163 Lacks CD1a CD163 Pan macrophage antigens: CD68, HAM56, CD14, CD64, CD15 Markers of lysosomal activity Markers of “activation” (IL2R/CD25, CD30?) Markers of cells derived from monocytes (rather than tissue macrophages); “activated histiocytes”

72 Differential Diagnosis
Reactive hyperplasia Hemato-lymphoid malignancy Metastasis Storage disorders Histiocytoses, particularly, LCH Reactive Inflammatory Infectious (EBV-associated/infectious mononucleosis) Granulomatous/necrotizing lymphadenitis Hematolymphoid Hodgkin and non-Hodgkin lymphoma Acute leukemia, especially lymphoblastic leukemia & monocytic leukemia Metastasis Carcinoma Sarcoma Germ cell tumors ( especially in children) Storage disorders Such as Gauchers with proliferation of foamy histiocytes Histiocytoses Reactive histiocytosis including hemophagocytic lymphohistiocytosis Malignant tumors of histiocytes and accessory dendritic cells Langerhans cell histiocytosis Examples are chosen to highlight reactive, metastatic and histiocytic (LCH) disorders.

73 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 Information on treatment is bases on retrospective study of registry patients, many of whom have incomplete data [Komp et al, Sem Diag Pathol 1990] Case reports and small series in the literature Objective measures of clinical response are lacking

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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