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White blood cell disorders


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  • 1. White Blood Cell Disorders Paul Basciano, MD March 2013
  • 2. Jack of all trades, master of none Certainly better than master of one
  • 3. Overview• Neutrophils: Neutropenia – Aquired: Immune and drug-induced – Congenital• Eosinophils: Hypereosinophilic Syndromes• Basophils/Mast Cells: Mastocytosis• Histiocytes – Hemophagocytic Syndrome – Langerhans Histiocytosis – Rosai-Dorfman
  • 5. Neutropenia• Peripheral blood ANC does not necessarily represent neutrophil pool: – Bone marrow, marginated in vessels, circulating blood (3%)• Therefore level ANC does not always correlate with risk of infection• Number of PMNS in reserves are what really matter – Also normal neutrophil function – Disease causing reduction in PMNs may cause increase in infectious risk per se• ANC can be a general guide; more sensitive than specific for risk of infection – Mild (ANC 1-1.5k/ul): Low risk – Moderate (ANC 0.5-1.0): Intermediate risk – Severe (ANC <0.5): Highest risk• Physical findings such as oral ulcers and gingivitis suggest a more severe neutropenia
  • 6. Causes of Neutropenia and Risk• Low risk neutropenias (adequate reserves): – Benign/ethnic – Hypersplenism – Post-infectious• Moderate risk neutropenias (questionable reserves): – Drug-induced – Infectious – Cyclic – Immune-mediated• High risk neutropenia (inadequate reserves): – Drug-induced – Infectious – Post-chemotherapy – MDS, myelofibrosis, aplastic anemia – LGL – Some congenital: Kostmann, Schwachman-Diamond
  • 7. Benign Ethnic Neutropenia• African americans, certain Jewish populations, certain Arab populations• Defective release from marrow• No increase in infectious risk, including after chemotherapy
  • 8. Infectious Neutropenia• Viral: all• Rickettsial diseases• Leshmaniasis, malaria• Bacterial: Typhoid, Shigella, Brucella, Tularemia, Tubercu losis
  • 9. Drug-Induced Neutropenia• Classics: antipsychotics (clozapine), antithyroid meds, sulfasalazine/sulfamethoxazole, and ticlopidine• Keep in mind: H-2 blockers, pretty much all antibiotics, TCAs, ACE-Is, antiarrhythmics, NSAIDs, dapsone, deferipone• Rituximab (30-175dd after dose)• Withdraw the offending agent (good luck finding it)—recovery can take 1-3 weeks• The role of GCSF is unclear; probably shortens duration, but of unclear overall benefit
  • 10. Immune Neutropenia• Circulating abs, normal marrow reserves: no risk of infection from neutropenia• Circulating abs, normal marrow reserves, underlying immunodeficiency: risk of infection from immunodeficiency• Circulating abs, normal marrow reserves, vasculitis: risk of infection from vasculitis/mucosal injury• Circulating abs/cytotoxic T cells, absent marrow reserves: high risk of neutropenic infections – LGL• BUT you don’t know risk if you don’t do a marrow…• Serologies or direct detection of abs on neutrophils is of very limited use – Questionable sensitivity and specificity; do not change managment
  • 11. AutoImmune Neutropenia and Chronic Idiopathic Neutropenia• Usually moderate degree of neutropenia (ANC 0.5-1)• AIN is primary (Chronic Benign Neutropenia) in most infants and secondary in most adults – Serologies of questionable utility – Normal bone marrow reserves – Usually resolves over time• CIN is more common in adults – Same clinical and diagnostic considerations – Does not resolve over time• Treatment is supportive; the role of GCSF remains unclear – Marrow reserves only adequate if maturation proceeds past meta-myelocyte stage – Steroids, IVIG—side effects likely outweigh benefits – Rituximab? Alemtuzumab? – What is driving the infection? The neutropenia or the underlying disease?
  • 12. Neutropenia and Primary Immunodeficiencies• Most primary immunodeficiencies will present in childhood• CVID is an exception – Severe reduction in IgG, some loss of IgA, IgM – Onset between puberty and age 30
  • 13. Congenital Neutropenias• Severe Congenital Neutropenia (incl Kostmann syndrome) – Severe, stable neutropenia – Generally respond to GSCF – Propensity for dysplasia and progression to AML – Multiple genes, including ELANE• Cyclic Neutropenia – 21d cycle of neutropenia lasting about 6 days – Severe neutropenia at nadir – Infectious and mucosal symptoms – ELANE mutation – Not a pre-leukemic state• WHIM: Warts, hypogammaglobulinemia, immunedificiency, myelokathesix (neurtrophils stuck in the marrow); CXCR4 mutation• Schwachman Diamond syndrome: SBDS (ribosome and microtubule protein): marrow hypoplasia, neutropenia, pre-leuekemic, pancreatic exocrine dysfucntion – N.b. this is NOT Diamond Blackfan anemia, which also involves a ribosomal protein• Chediak-Higashi: albimism, platelet granule disorder (dense bodies), neutrophil inclusions, progression to multisystem disease with histiocytosis
  • 14. Disorders of Neutrophil FunctionDisease Gene CharacteristicsMPO deficiency MPO -Most asymptomatic; maybe increase in CandidaLAD deficiency Intergrins -Delayed wound healing ITGB2 -Neutrophilia FUCT2 -Recurrent bacterial infections FERMT3 -Some have platelet disordersChronic Granulomatous NADPH -Skin and lung infections (Aspergillus,Disease oxidase Burkholderia, S aureus, Nocardia, genes Mycobacteria) -Dihydrorhoadmine 123 flow assay or burst nitroblue tetrazolium testJob syndrome (HyperIgE) STAT3 Skin, lung, sinus infections, Candida infections High IgE levels
  • 16. Hypereosinophilic Syndrome• A broad syndrome with varying clinical manifestations and etiologies• New revised criteria: – Acknowledges importance of peripheral blood eosinophilia as early disease, as well as some syndromes to have tissue damage without peripheral blood eosinophilia
  • 17. **EAEs: Churg-Strass, Angioedema with eosinophilia, Eosinophilia-associated GIdisorers, eosinophilic pneumonia, eosinophilic fasciitis
  • 18. Primary work-up of eosinophilia• For both exclusion of secondary causes as well as identification of organ involvement• Complete history: travel history, drug history• Exam (rashes, joints, muscles/fascia)• IgE, B12 levels, tryptase• HIV serology, stool parasite screen, strongyloigdes serologies• EKG, Echo, PFTs• CT C/A/P• Bone marrow aspirate and biopsy
  • 19. -Days to years after initiation-May have tissue restrictedmanifestations(nephritis, myositis, DRESS-Often difficult to find offendingagent-May take months to resolve -Strongyloidiasis: may have hyperinfection with steroid treatment; consider empiric treatement prior to steroids
  • 20. **EAEs: Churg-Strass, Angioedema with eosinophilia, Eosinophilia-associated GIdisorers, eosinophilic pneumonia, eosinophilic fasciitis
  • 21. Myeloproliferative Variant• Based on rearrangements involving the PDGFRA gene – Classically and most common FIP1L1-PDGFRA MPN M-HES Mastocytosis (Chronic Eosinophilic Leukemia) JAK2V617F PDGFRA- D816KIT • RT-PCR or CHIC2 deletion by FISH FIP1L1 – Multiple others identified (PDGFRB, FGFR1)—need specialized testing• Clinical presentation: – Dysplastic eos, splenomegaly, anemia, thrombcotyoepnia, bon e marrow fibrosis/hypercellulartiy, atypical mast cells, increased tryptase, eosinophil-related tissue damage and fibrosis • Overlap between MPN, M-HES, and mastocytosis • True diagnosis may be difficult to make
  • 22. Lymphocytic-Variant MES• Clonal populations of activated, phenotypically-aberant T lymphocytes (CD3-CD4+)• More protracted course• More dermatologic, GI, and lung – Less fibrotic manifestations• Progression to lymphoma is possible (T-cell lymphoma)
  • 23. HES: Treatment• Corticosteroids – Rapid reduction of eosinophil counts (within hours) – More likely useful in I-HES and L-HES; M-HES unlikely to respond – Doses variable • 1-2mg/kg prednisone for high risk of morbidity • 0.5-1mg/kg for more indolent disease• Hydrea – Most often combined with other agents – Acts centrally, and leads to slow reduction in eos – 500mg-2g daily; GI and hematologic side effects >1g/d• IFN-a – Slow effects – Slow up-titrating in dosing – PEG-IFN-a likely as efficacious and less side effects – Likely useful in all subtypes of F/Pneg HES (including L-HES)
  • 24. HES: Imatinib• Multi-TKI• Likely useful for all CEL rearrangements• F/P fusion protein 100-fold more sensitive than BCR-ABL• Relatively rapid effect (1 week) with reversal of most effects except cardiac fibrosis• Should be used with steroids in patients with cardiac involvement• Mirrors CML with effects, clone clearance, need for continuous treatment, evolution of resistant clones• Definite utility in CEL; worth a try in M-HES and I-HES (higher doses); unlikely to work in L-HES
  • 25. HES: Anti-IL-5• Mepolizumab – Induces rapid clearence of peripheral blood eos – Long lastin effect (3mos) but not curative – Allows tapering of steroid therapy – Only available in compassionate-use trial for patients with lifethreatening disease and failure of three other agens
  • 26. HES: Kitchen Sink• Cytoxan, MTX, Vincristine, chlorambucil• Alemtuzumab—possibly useful, highly toxic• Transplant
  • 27. High dose IV +/- empiric parasiteLife/Limb Threatening steroids treatmentComplications + Imatinib (if c/w M-HES) F/P+ Imatinib 100mg Refractory or Other TKIs, otherCEL resistance Imatinib 400mg development therapies, SCT No F/P, Cardiac Sxs with taper+ PredSymptomatic Response Taper; +/- HU, IFNa SteroidsI-HES Failure Imatinib 400mg Failure Kitchen (short course) SinkSymptomatic Steroids, +/-L-HES IFNa
  • 28. MAST CELLS
  • 29. Mastocytosis• Clonal disorder of mast cells usually driven by mutations in c-KIT – Release multiple mediators from granules associated with allergic-type symptoms, fibrosis, vasodilation, expansion of other blood cells) • Disease is driven by mediator-release symptoms and infiltration/fibrosis• Two main forms: – Cutaneous – Systemic: • Indolent • Aggressive (with tissue dysfunction) • Mast cell leukemia • Associated with hematologic non-mast cell lineage disorder (MPD, MDS, lymphoid)
  • 30. Mastocytosis• Manifestations(in both cutaneous and systemic) – Cutaneous • Urticaria pigmentosa • Telangiectasia, bullous lesions, Darier’s sign – Mediator release symptoms: • Anaphylaxis (IgE or non-specific; seen in Cutaneous and Systemic) • GI: Abd pain, nausea, vomiting, diarrhea, bleeding, ulcers (histamine) • Neuropsychiatric • Musculoskeletal: pain, osteopenia• Infiltrative symptoms/signs: – Hepatosplenogmealy – Anemia, thrombocytopenia – Malabsorption – Lytic bone lesions• Associated blood findings: eosinophilia, monocytosis
  • 31. Trigger of Mediator Release• Exercise, massage, spicy food, heat and cold• Surgery, instrumentation• Alcohol• Medications: narcotics, NSAIDs, contrast, Vancomycin, Ceph alosporins• Emotional stress• Bites, stings, venoms
  • 32. Diangosis• Skin and organ biopsies; bone marrow biopsy – Mast cell morphology (spindle); tryptase staining – Immunophenotype: CD25, CD2, CD117• Imaging of bones and viscera• Serum markers – Typtase: also elevated after anaphylactic reaction, AML, CML, MDS, CEL• D816V KIT mutation analysis (marrow)• Patients with symptoms of mast cell mediator release, OR unexplained organomegaly, OR cutaneous findings c/w mastocytosis should undergo bone marrow biopsy
  • 33. Treatment• Mast cell mediator symtpoms: – Preparation to treat anaphylaxis (EpiPen) – Avoidance of triggers – Pre-treatment for unavoidable triggers: • H2 + H1 blocker +/- moneluekast• Indolent systemic: no mast cell treatment needed – Monitor for progression – Treat for mast cell mediator symptoms
  • 34. Treatment• Aggressive systemic mastocytosis – IFNs: 30-50% ORR; toxicities limit treatment; treatment response may takes weeks to months – Cladribine: 60% ORR; myelosuppression and infection; most will relapse; use after INFs – Imatinib: D816V KIT mutations will not respond; other mutations or WT KIT may respond; other TKIs are investigational – Hydrea – Transplant: role unlcear; especially for mast cell leukemia• Mast cell leukemia: full leukemia treatment
  • 35. Langerhans cellsMonocytes/MacrophagesDendritic CellsHISTIOCYTES
  • 36. Hemophagocytic Lymphohistiocytosis• Condition of high inflammatory cytokines, T cell activation, and histiocyte/macrophage activation• Fever, cytopenias, splenomegaly• Most will have liver inflammation/hepatitis• Bleeding is common (DIC, platelet dysfunction)• CNS dysfunction is common• Primary (familial) associated with perforin gene mutations in 50%; also congenital immunodficiencies• Secondary associated with malignancy, immune compromise, rheumatologic disorders (Still disease- >Macrophage activation syndrome)Often not seen early in disease, sometimes seen after response
  • 37. HLH
  • 38. Langerhans cell Histiocytosis• Infiltrative disease of Langerhans-like cells• Can be unifocal or multifocal, and single-organ or multi-organ – Bone is most common • Lytic lesions • Bone pain/swelling • Loose teeth, cranial involvement (DI, pituitary disturbance) – Skin – LN, BM – Hepatosplenomegaly – Pulmonary
  • 39. LCH• Diagnosis is made by biopsy – Typical morphology (eosinophilic, coffee bean nuclei) – S100, CD207 (langerhin, Birbeck granules), CD1a• Treatment is by aggressivity: – Single organ: observe, remove, or limited immune suppression – Multi-organ, progressive, or high risk (BM, lung, liver involvement): systemic therapy, transplant
  • 40. Other histiocyte disorders• Erdheim-Chester: non-Langerhans histiocytes; abnormal morphology; sclerotic bone lesions• Rosai-Dorfman (sinus histiocytosis with massive lymphadenopathy) – Non-malignant disorder – Massive lymph nodes or solitary masses in tissues (sinuses, mucosa) – Treatment is observation versus other (MTX, IFN) based on symtpoms – Characteristic emperipolesis (lymphocytes and other cells passing through/resting in histiocyte cytoplasm)