Bone Marrow Morphology after Therapy and Stem Cell Transplantation. Arash Mohtashamian, MD Naval Medical Center, San Diego

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1 Bone Marrow Morphology after Therapy and Stem Cell Transplantation Arash Mohtashamian, MD Naval Medical Center, San Diego

2 Objectives Bone marrow findings after myeloablative therapy. Effects of recombinant cytokine therapy (e.g. G-CSF). Bone marrow changes following treatment with Imatinib Mesylate (Gleevec). Bone marrow changes following treatment with Rituximab (chimeric anti-cd20 antibody). Effects of bone marrow transplantation.

3 Reasons for bone marrow biopsy after therapy Degree of tumor ablation/minimal residual disease testing Persistent cytopenias: appropriate hematopoietic regeneration? Disease recurrence. Post therapy associated hematopoietic neoplasms.

4 Factors limiting post-therapy BM Hemodilution interpretation Absence of particles on the aspirate smears No previous biopsy material available for comparison Small bone marrow biopsy Aspiration artifact Sampling of previous biopsy site

5 Additional considerations in bone marrow interpretation Patient specific genetic make-up (pharmacogenomic) Tumor cell genetic make-up Dose of drug and types of drug administered

6 Objective 1: Bone marrow changes after myeloablative therapy

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8 Early (1-2 week) Mid (~2-4 weeks) Late (~3-6 weeks) Marrow aplasia, virtually acellular Diffuse fibrinoid necrosis w/wo tumor necrosis Dilated sinuses Marked edema Absence of fat cells Rare stromal cells, lymph, plasma cells, histiocytes Reappearance of fat cells, multiloculated Slight reticulin fbrosis (transient) Early erythroid islandsleft shifted maturation Granulocytic precursorstypically next to bony trabeculae May see increased hematogones Multilineage hematopoietic regeneration Normal or hypercellular marrow Resolution of reticulin fibrosis May see megakaryocytic clustering Bone Marrow Pathology, Third Edition (2 Vol set) bykathryn Foucar, Kaaren Reichard, David Czuchlewski

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11 Knowles Neoplastic Hematopathology By Attilio Orazi, Kathy Foucar, Daniel Knowles, Lawrence M. Weiss

12 Uncommon bone marrow findings after myeloablative therapy Transient blastemia Marked hematogone hyperplasia Sheets of promyelocytes Therapy induced maturation of neoplastic cells Sheets of megakaryocytes Surge of PB blasts during early BM reconstitution, BM blasts <1%, linked to subsequent relapse & poor outcome Typically pediatric bone marrow, nonclonal Distinction from lymphoblasts possible by flow cytometry Granulocytic regeneration may result in cells at same stage of maturation May be confused with recurrent or residual AML Occurs in APL following ATRA, may resemble monocytic cells Transient following induction chemo for AML Fibrosis with or w/o bony changes Lack of hematopoietic regeneration Typically in blasts phase of a myeloproliferative neoplasm, may be associated with new bone formation Delayed or failed, idiosyncratic reaction to chemo typically in elderly patient Bone Marrow Pathology, Third Edition (2 Vol set) bykathryn Foucar, Kaaren Reichard, David Czuchlewski

13 Knowles Neoplastic Hematopathology By Attilio Orazi, Kathy Foucar, Daniel Knowles, Lawrence M. Weiss Charcot Leyden crystals associated with acute myeloid leukemia: Case report and literature review Charcot Leyden crystals associated with acute myeloid leukemia: Case report and literature review. Tallman, Martin S. Published Z.Volume 34, Issue 12.Pages e336-e

14 Objective 2: Effects of recombinant cytokine therapy

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16 Hematologic and Biochemical Effects Reported during Short Courses of G-CSF and GM-CSF in Phase I Studies in Patients with Advanced Cancer.* Lieschke GJ, Burgess AW. N Engl J Med 1992;327:28-35.

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21 Objective 3: Bone marrow changes following therapy with Imatinib Mesylate (Gleevec)

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29 Objective 4: Bone marrow changes following treatment with Rituximab

30 Benign versus neoplastic lymphoid aggregates Benign Rounded aggregates Well circumscribed, regular, small lymphs Elderly population <3mm in diameter Never paratrabecular Germinal centers May contain plasma cells and eos Polytypic light chain expression 1-3 aggregates per core biopsy Neoplastic May be irregular Cellular atypia may be present Wide age range May be >3mm diameter No germinal centers Usually just lymphoid cells Monoclonal light chain pattern >3 aggregates per core biopsy

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32 Rituximab Chimeric anti-cd20 antibody used in combination with conventioanl chemo (CHOP) to treat de novo or relapsed NHL. Also used in treatment of autoimmune disorders. Complement dependent cytotoxicity, antibody depenedent cellular cytotoxicity, and induction of apoptosis

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40 Objective 5: Bone marrow changes after stem cell transplantation

41 Disorders that may be treated with ASCT Non-neoplastic Aplastic anemia Bone marrow failure syndrome (eg, Fanconi anemia) NPH Chronic granulomatous disease Myelofibrosis Immune deficiency states Thalassemia and sickle cell disease Mucopolysaccaridoses Neoplastic Acute leukemias CML, BCR-ABL+ CLL/SLL Hodgkin and NHL

42 Kinetics of engrafment Source of donor cells Dose of infused cells Use of recombinant cytokines Degree of HLA mismatch Non-HLA polymorphisms may also affect the outcome

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44 Histologic features of bone marrow after successful transplant Time after transplantation Morphologic features Day 0-7 Cell death and necrosis Stromal damage, fat necrosis, and edema Hemosiderin laden macrophages Transient reticulin fibrosis and small non-caseating graulomas Day 8-14 Early immature hematopoietic non-paratrabeculae colonies Multiloculated fat lobules and adipocyte regeneration Day Expansion of immature hematopoietic elements with maturation May see transient dysplasia, may be persistent By day 28 cellularity is ~50% of normal Resolution of fibrosis and fibrinoid necrosis Months 2-3 Multilineage hematopoiesis complete Normocellular

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47 Complications of hematopoietic stem cell transplantation (typically declining cell count after day 28) Disease related Persistent disease Myelofibrosis Disease relapse or transplantation during relapse Therapy related Delayed or failed graft engrafment Drug toxicity GVHD Development of therapy related neoplasms PTLD Bone marrow damage due to chemo Infection Viral (EBV, VAV, CMV, HSV) Fungal or bacterial Other Florid hematogone hyperplasia Development of donor drived neoplasms Development of solid cancer Avascular necrosis of bone marrow

48 GVHD involving bone marrow Donor graft T-cells reacting against antigens in immunocompromised host. Skin, liver, and GI tract typically primary sites targeted by GVHD No pathogenomic alterations in bone marrow, usually non-specific findings: - fibrosis, histiocytic proliferation, hypoplasia

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50 Key components of bone marrow report after therapy Include the original diagnosis Type and duration of therapy Current bone marrow status Ancillary studies (cytogenetics, FISH or PCR) Findings pertaining to any specific clinical question (eg. Residual disease, etiology of possible cytopenia, possible infection, etc)

51 Other medications worth considering Lenalidomide (immunomodulatory agents), also include thalidomide and pomalidomide- treatment of MDS and myeloma Azathioprine- immunosuppressive agent for various autoimmune disorders Zidovudine (AZT)- multilineage bone marrow suppression, may cause PRCA, BM hypoplasia, neutropenia Valproic acid- anti-epileptic agent, transient myeloid, erythroid and megakaryocytic dysplasia Others

52 The end