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CP UNKNOWN Reeba Omman, PGY-1 Dr. Girish Venkataraman Dr. Philip DeChristopher.

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Presentation on theme: "CP UNKNOWN Reeba Omman, PGY-1 Dr. Girish Venkataraman Dr. Philip DeChristopher."— Presentation transcript:

1 CP UNKNOWN Reeba Omman, PGY-1 Dr. Girish Venkataraman Dr. Philip DeChristopher

2 59/M PB smear from core lab for path review: Funny looking immature cells?

3 What should be the next step in the work up? 1.Review the entire smear 2.Flow? 3.Review the chart-for what? 4.Pick up the phone and call clinician with blasts in blood?

4 59 y/o hispanic male DLBCL of stomach in 01/2010 Completed 6 cycles of CHOP 6/2010 Follow up EGD 9/9/2011 suggestive of recurrent disease 10/2011 – PET scan shows increased uptake in fundus and adjacent lymph node s/p one cycle of ICE (ifosfamide, etoposide and carboplatin) finished 3 weeks ago Presents for cycle 2 of ICE Clinical History-11/16/2011

5 LymphomaLymphoma LeukemiaLeukemia Systemic/Organ specific infectionSystemic/Organ specific infection –Bacterial, fungal, viral DrugsDrugs –G-CSF –Valproic acid, Ganciclovir

6 Toxic granulation with Dohle bodies Additional areas of the same smear

7 Toxic Vacuolization Additional areas of the same smear

8 Left shift leukocytosis

9 More pertinent patient History Patient asymptomatic, afebrile, blood cultures negative On Neulasta (Peg-G-CSF) since 10/30/2011 Diagnosis: –G-CSF related toxic changes and rare blasts in peripheral blood smear

10 What is G-CSF? Granulocyte Colony Stimulating Factor –Glycoprotein –Growth factor –Cytokine Produced by endothelium, macrophages and other immune cells G-CSF receptor present on precursor cells in the bone marrow –Initiates proliferation and differentiation into mature granulocytes –Stimulates bone marrow cell release into circulation

11 G-CSF regulates them using Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and Ras /mitogen- activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signal transduction pathway.Janus kinase (JAK)/signal transducer and activator of transcription (STAT)mitogen- activated protein kinase phosphatidylinositol 3-kinaseprotein kinase B

12 FILGRASTIM (G-CSF) regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, differentiation and functional activation PEGFILGRASTIM (Pegylated G-CSF) –pegylated form of recombinant filgrastim –covalently binding 20-kD pegylated molecule to the N- terminus of filgrastim SAGRAMOSTIM (GM-CSF) stimulates myelopoiesis generally, and neutrophils and monocytes specifically Types of Colony Stimulating Factors

13 Two important G-CSF uses 1.MOST COMMON: Post chemotherapy febrile neutropenia –2006 ASCO Update on CSF use – Evidence Based Clinical Practice Guideline When the risk of febrile neutropenia is 20% and no other equally effective regimen is available –Age –Medical History –Disease characteristics –Myelotoxicity of the chemotherapy regimen –Does not compromise dose intensity –Reduces dose delays 2.Potent inducer of hematopoietic stem cell mobilization for stem cell transplantation (SCT)

14 G-CSF (Filgrastim) Pegylated G- CSF (Pegfilgrastim) GM-CSF (Sargramostim) Clinical Use -after 24 hrs -daily dose for days -lasts 24 hrs -for inpatients -one dose -2 weeks -for outpatients (billing issue) -similar to G-CSF -rare -after BM transplant if patient has invasive fungal infection (increases monocytes) G-CSF and post chemotherapy FN

15

16 Left Shift Leukocytosis

17 Toxic Granulation Large purple or dark blue granules –Similar to primary granules of promyelocytes, metamyelocytes, bands and segmented neutrophils –That are retained in mature neutrophils –More deeply staining than normal Due to enhanced lysosomal enzyme production and packaging –Associated conditions: Infection, trauma, burns

18 Dohle Body In association with neutrophil activation: toxic granulation and vacuolization Single or multiple blue to gray blue inclusions of variable size and shape Denatured aggregates of free ribosomes or stacks of rough endoplasmic reticulum Usually in neutrophils, bands and metamyelocytes Associated conditions: –May-Hegglin anomaly, Alder’s anomaly, infection, trauma, burns, pregnancy

19 Toxic Vacuolization Round clear spaces in cytoplasm –Sites of digestion of phagocytized material Larger and more numerous; may coalesce and appear to disrupt the cytoplasm More prominent vs. degenerating neutrophils Associated conditions: –May-Hegglin anomaly, Alder’s anomaly, infection, trauma, burns and pregnancy

20 G-CSF/Pegylated G-CSFGM-CSF Peri- pheral blood smear Marked leukocytosis secondary to neutrophilia Rare giant (tetraploid) neutrophils present Prominent toxic changes of neutrophils, vacuoles prominent Nuclear-cytoplasmic asynchrony Nuclear segmentation abnormalities Left shift with circulating blasts Circulating myeloid cytoplasmic fragments Marked leukocytosis with increase in neutrophils and monocytes, with variable increase in eosinophils, lymphocytes, and sometimes basophils Prominent toxic changes in mature and immature granulocytes Left shift with circulating blasts (usually low percent) and erythroblasts Nuclear-cytoplasmic asynchrony Nuclear segmentation defects Bone marrow Early: interstitial foci of granulocyte precursors in hypocellular bone marrow Increased cellularity with left shift in hematopoietic elements Promyelocytic hyperplasia with reactive features during early phase of therapy Pronounced toxic changes of immature and mature granulocytic elements Occasional binucleate promyelocytes and myelocytes Rare: fibrosis with bony changes, acute bone marrow necrosis Histiocytic proliferation (GM-CSF plus G-CSF)

21 Peripheral blood stem cell mobilization (PBSC) Advantage of PBSCs over steady-state marrow stem cells has more rapid hematologic reconstitution following transplantation G-CSF is standard mobilizing agent (other agents are chemotherapy and chemokines) –Mobilizes more CD34+ with less toxicity –G-CSF > Peg G-CSF

22 G-CSF and PBSC Mobilization On Day 4 or 5 after G-CSF therapy, peripheral blood CD34 level is measured If CD34 level is above (5-20 CD34 cells/uL), apheresis begins Poor mobilization factors: –Increasing age, increasing cycles and regimens of chemotherapy, prior radiation to active marrow sites, prior treatment with purine analogues, female gender Side effects: –Injection site erythema, bone pain, HA, fever, splenic rupture (rare)

23 Advantages –Predictability of apheresis CD34 cells enter circulation on 4 th or 5 th day –Combination of G-CSF and GM-CSF is good for “poor mobilizer” population 10 or more cycles of chemotherapy, platinum- based chemotherapy, radiation to marrow sites G-CSF and PBSC Mobilization

24 Pheresis collection post G-CSF therapy

25 References 2006 Update of ASCO Practice Guideline Recommendations for the Use of White Blood Cell Growth Factors: Guideline Summary. Journal of Oncology Practice, vol 2. July ASH Image Bank. American Society of Hematology Publications. “Blast crisis: Differential Diagnosis” BMJ Publishing Group Limited practice/monograph/1026/diagnosis/differential.html practice/monograph/1026/diagnosis/differential.html “Benign White Cell Disorders: Leukocytosis” Pathology Thread. University of Virginia School of Medicine. ed.virginia.edu/courses/path/innes/wcd/leukocytosis.cfmhttp://www.med- ed.virginia.edu/courses/path/innes/wcd/leukocytosis.cfm Glassy, Eric F. Color Atlas of Hematology. CAP Hematology and Clinical Microscopy Resource Committee Wingard et al. Hematopoietic Stem Cell Transplantation. AABB. Bethesda, Maryland “Neuroprotective effect of Granulocyte colony stimulating factor” Frontiers in Bioscience 12, , January http://www.bioscience.org/2007/v12/af/2095/fulltext.asp?bframe=viewer. htm&doi=yes


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