Bone Marrow Morphology after Therapy and Stem Cell

Transplantation

Arash Mohtashamian, MD

Naval Medical Center, San Diego

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.

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.

Factors limiting post-therapy BM

interpretation

• Hemodilution

• 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

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

Objective 1: Bone marrow changes after

myeloablative therapy

Early (1-2 week) Mid (~2-4 weeks) Late (~3-6 weeks)

Marrow aplasia, virtually acellular

Reappearance of fat cells, multiloculated

Multilineage hematopoietic regeneration

Diffuse fibrinoid necrosis w/wo tumor necrosis

Slight reticulin fbrosis (transient)

Normal or hypercellular marrow

Dilated sinuses Early erythroid islands- left shifted maturation

Resolution of reticulin fibrosis

Marked edema Granulocytic precursors- typically next to bony trabeculae

May see megakaryocytic clustering

Absence of fat cells May see increased hematogones

Rare stromal cells, lymph, plasma cells, histiocytes

Bone Marrow Pathology, Third Edition (2 Vol set) byKathryn Foucar, Kaaren Reichard, David Czuchlewski

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

Uncommon bone marrow findings

after myeloablative therapy Transient blastemia Surge of PB blasts during early BM reconstitution, BM

blasts <1%, linked to subsequent relapse & poor outcome

Marked hematogone hyperplasia Typically pediatric bone marrow, nonclonal Distinction from lymphoblasts possible by flow cytometry

Sheets of promyelocytes Granulocytic regeneration may result in cells at same stage of maturation May be confused with recurrent or residual AML

Therapy induced maturation of neoplastic cells

Occurs in APL following ATRA, may resemble monocytic cells

Sheets of megakaryocytes Transient following induction chemo for AML

Fibrosis with or w/o bony changes Typically in blasts phase of a myeloproliferative neoplasm, may be associated with new bone formation

Lack of hematopoietic regeneration 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

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 2010-12-01Z.Volume 34, Issue 12.Pages e336-e338.© 2010.

Objective 2: Effects of recombinant

cytokine therapy

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.

Objective 3: Bone marrow changes following therapy with

Imatinib Mesylate (Gleevec)

Objective 4: Bone marrow changes

following treatment with Rituximab

Benign versus neoplastic lymphoid

aggregates

Benign Neoplastic

• 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

• 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

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

CD20

Objective 5: Bone marrow changes after

stem cell transplantation

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

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

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 15-28 • 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

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

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

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)

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

The end