Cancers of the Bone Marrow: A Clinical Perspective Mary Ward, RN, BS, CTR.

Cancers of the Bone Marrow: A Clinical Perspective

Mary Ward, RN, BS, CTR

Objectives

• To increase the Cancer Registrar’s knowledge of the disease process of select cancers of the bone marrow from a clinical perspective

• Discuss the pathogenesis, clinical evaluation and treatment options of AML, APL, MDS and Multiple Myeloma

• Describe clinical distinctions that correspond with some of the ICD-0-3 codes for patients diagnosed with AML

What does the Bone Marrow Do?• Produces all the elements of the

blood– RBCs– Platelets– WBCs

• Proliferating marrow is found in certain areas of the body of adults

Cancers that Affect the Bone Marrow

• Myelodysplastic Syndromes• Leukemias• Lymphomas*• Plasma Cell Myelomas

Case Presentation: JF

• 68 yo wmm presents to PCP– c/o fatigue, malaise x 6 weeks, ill-defined

fevers and intractable infection • infection treated with abx x2; • weight loss of 10 lbs, decreased appetite, easy

bruising on his extremities

• PE revealed wm in no acute distress; presents with nonproductive cough, fever of 101.9o, no lymphadeopathy, noted several small bruises on LT arm and RT leg; no ictera, no jaundice;

Case Presentation: JF

• Chest x-ray• CT abd • Labs: CBC with differential and CMP• Peripheral blood smear

Case Presentation: JF

• JF is admitted to the inpatient oncology unit at Home Base Hospital

• Ongoing diagnostic workup would include:– Uric Acid level– Bone Marrow biopsy and aspirate– Leukemia and Lymphoma panel– HLA typing– Type and Cross for transfusions

• Consult to Heme/Onc

AML: Defined

• A group of hematopoietic neoplasms that affect the precursor cells of the myeloid cell line

• The proliferation of the precursor cells causes a reduced capacity of the mature cells to develop

Epidemiology and Risk Factors

• Most common acute leukemia in adults

• Median age at diagnosis is 65 years old

• Male to female ratio of 5:3

Risk Factors

• Environmental – Chemicals– Radiation– Tobacco– chemotherapy drugs

• Genetic abnormalities– Trisomy 21, Fanconi’s anemia, Bloom’s

syndrome

AML: Diagnostic Workup

• Peripheral blood smear• Bone marrow aspiration and biopsy*• Cytogenetics*• Immunophenotyping*

AML ClassificationFAB WHO Histology Code

M0 AML with minimal differentiation 9872/3

M1 AML without maturation 9873/3

M2 AML with maturation 9874/3

M3 Acute promeylocytic leukemia with t(15:17) q(22;q12) PML-RARA

9866/3

M4 Acute myelomonocytic leukemia 9867/3

M5a Acute monoblastic/acute monocytic leukemia

9891/3

M5b Acute monoblastic/acute monocytic leukemia

9891/3

M6 Acute erythroid leukemia

M7 Acute megakaryoblastic leukemia 9910/3

AML with Recurrent Genetic Abnormalities

AML with t(8;21)(q22;122), RUNX1-RUNX1T1

Favorable prognosis in adults; seen in younger adults overall

9896/3

AML with inv (16)(p13q22) or t(16;16)(p13;q22), CEFB-MYH11

Favorable prognosis with standard therapy

9871/3

AML with t(9;11)(p22;q23); MLLT3-M-LL

Unusual age distribution-seen in ¾ of children >1 yr old; very poor prognosis

9897/3

AML with t(6;9)(p23;q34); DEK-NUP214

High rate of FLT3-ITD mutations which is conveys a poor prognosis

9865/3

AML with inv (3)(q21q26:2) or t(3;3)(q21;126:2); RPN1-EV11

Commonly presents with increase megakayocytes, many morphologically abnormal

9869/3

AML (magakayoblastic) with t(1;22)(p13;q13;q13); RBN15-MKL1

Rare; sometimes presents as a mass and mimics sarcoma

9911/3

AML with Recurrent Genetic Abnormalities

• Codes that do not need a 20% blast for definitive diagnosis:– AML with t(8;21)(q22;q22), RUNX1-

RUNX1T1– AML with inv(16)(p13q22) or t(16)

(p13;q22), CEFB-MYH11– APL with t(15;17)(q(22;112), PML-RARA

Treatment Planning

• Standard Treatment– Induction chemotherapy 7+3 regimen

• Cytarabine plus an anthracycline

– Post Remission Treatment: based on Risk Stratification

• Hematopoeitic Stem Cell Transplant• Consolidation chemotherapy: HDAC: high-

dose Ara-C, cytarabine-one dose every 28 days for 3-4 doses

Factor Favorable Unfavorable

Age <50 years >60 years

Leukemia De novo secondary

WBC <25,000 >100,000

FAB subtype M3, M4 M0, M5, M6, M7

Cytogenetics T(15;17), t(8;21) in(16) normal: RUNX1-RUNX1T1;

Abnormalities of chr. 5, 7, multiple, >3 abnormalities; 11q23, t (6;9); inv 3

Extramedullary disease

Absent present

Auer rods Present Absent

Phenotype CD 34- CD34+;CD56+

Other Nucleophosmin 1 (NPM-1), CEBPA

FLT-3 mutation; KIT mutations

The Older Adult with AML

• Factors that contribute to poor outcomes:– Poorer performance status– Higher incidence of multidrug resistance– Lower percentage of favorable cytogenteics– Higher percentage of unfavorable cytogenetics– Higher treatment-related morbidity and

mortality– Higher incidence of treatment-resistant disease– Lower complete remission rates, shorter

remission durations, shorter median overall survival

– Fewer opportunities for allo HCT

Treating the Older Adult with AML• Favorable or intermediate risk

patients– Induction therapy 7+3 regimen

• Unfavorable risk or patients with significant comorbidities– Supportive care

• Transfusions, antibiotics, low-dose chemotherapy

AML Coding Tips

• Histology Coding – Enter a provisional diagnosis, NOS, until a

more specific diagnosis is made– There is no time limit

• Treatment Coding– 1st course treatment includes all remission-

inducing and remission-maintaining therapies

– Treatment can span a year or more– Supportive care is not coded as treatment

Acute Promyelocytic Leukemia

• Biologically and clinically distinct variant of AML– FAB classification of AML-M3– WHO classification: APL with t(15;17)

(q24.1;q21.1); PML-RARa (9866/3)

• Incidence: 5-8% of all AML cases • Age-predominately adults in mid-life

Clinical Manifestations of APL

• Presents as a clinical emergency with a high rate of early mortality– Often due to hemorrhage from coagulopathy

• Presenting symptoms typically secondary to pancytopenia: anemia, neutropenia, thrombocytopenia– Easy fatigability– Infections– Bleeding

• Bleeding for APL patients may be secondary to DIC

APL and DIC

• APL is often manifested by Disseminated Intravascular Coagulation– DIC is a cascade of bleeding and micro clotting

that leads to a depletion of clotting factors and platelets

• Ultimately it leads to hemorrhage in various sites in the body

– This is a medical emergency • Untreated it may lead to pulmonary or cerebral

hemorrhage and possible death due to hemorrhage

– May be present at diagnosis or at initiation of cytotoxic therapy

– Induction of therapy improves condition

Diagnostic Criteria of APL

• Suspected by the characteristic morphology of the leukemic cells

• Presence of severe coagulopathy• The Non-granular form of APL

presents with leukopenia• Diagnosis is confirmed by testing for

the characteristic PML-RARA fusion gene or associated chromosomal translocation– Usually by FISH testing

Treatment of APL

• May span 1-2 years total– Remission induction– Consolidation– Maintenance

Treatment of APL

• Induction– Treatment should be initiated as soon as APL is

suspected• Median survival of <1 month without treatment

– ATRA-Retinoic Acid• Mechanism: induces tumor cell differentiation and

maturation• If the patient is found to have another type of

leukemia, ATRA will be d/c’d

– Plus chemotherapy• An anthracycline and possibly Cytarabine

Treatment of APL

• Consolidation: – Arsenic Trioxide followed by a

combination of an antrhacycline plus ATRA

• Maintenance– ATRA daily for one year

Coding Tips for APL

• APL is considered a distinct variant of AML and should be coded as such

• Per the SEER Antineoplastic Drug Database– ATRA is coded

• Code under “Other Treatment” and code as (1), Cancer treatment not otherwise assigned

– Arsenic Trioxide is not a coded drug at this time

• The precise mechanism of action has not been fully determined

MYELODYSPLASTIC SYNDROMES

Myelodysplastic Syndromes

• Group of heterogeneous malignant hematopoietic stem cell disorders

• Characteristics– Dysplastic and ineffective blood cell

proliferation – Variable risk of transformation to acute

leukemia

• May occur de novo or after exposure to mutagenic therapy (radiation, chemotherapy)

MDS: Epidemiology and Risk Factors

Age distribution Median age at diagnosis: 65

Gender Male predominance

Environmental risk factors: Chemical exposure: benzene, radiation, tobacco, chemotherapy drugs)

Genetic risk factors trisomy 21, Fanconi anemia, Bloom syndrome

Comorbid conditions as risk factors

Benign hematologic diseases (paroxysmal nocturnal hemagloinburia, congenital nuetropenia)

Clinical Presentation of MDS

• Non-specific signs and symptoms– Many patients are asymptomatic

• Most common presenting signs are from a cytopenia– Anemia is the most common cytopenia– Infection is a less common presentation

Diagnostic Criteria of MDS

• Clinical evaluation with pathologic evaluation of peripheral blood and bone marrow

– Unexplained changes at least one lineage that quantifies as a cytopenia

– Morphologic dysplasia on visual inspection

– Blast forms <20% of total cells

Types of MDS

Refractory anemia <5% blasts; only anemia 9980/3

Refractory neutropenia

>10% dysplastic neutrophils 9991/3

Refractory thrombocytopenia

>10% dysplastic megakaryocytes; cytogenetic studies helpful

9992/3

Refractory anemia with ring sideroblasts

>15% ring sideroblasts in BM; <5% blasts in peripheral blood;

9982/3

Refractory anemia with multilineage dysplasia

Bi-cytopenia/pancytopenia and dysplastic changes in 2 or more myeloid lines

9985/3

Refractory anemia with excess blasts

Multiple types based on blast percentage from 1-19%

9983/3

MDS associated with isolated del 5q

Associated with specific genetic abnormality

9986/3

MDS: Chromosomal Abnormalities• Most common:

– Del(5q), -7, trisomy 8, del (20q) and loss of the Y chromosome

• Single or multiple chromosomal changes may be present at the time of diagnosis

• Chromosomal changes may occur during the course of the disease

Do not change the coding of MDS once the initial diagnosis has been made

MDS: 5q-Syndrome

• Distinctive profile– Median age at diagnosis is 65-70 years– Female predominance of 7:3

• Typical presentation – refractory macrocytic anemia– normal or elevated platelets – absence of neutropenia

• Benign course of disease– Projected median survival is 63 months– Likelihood of transformation to AML is low

Classification of MDS-IPSS-R

• International Prognostic Scoring System-Revised– Calculates prognosis based on:

• Bone marrow blast percentage • Karyotype (very good, good, intermediate,

very poor)• Hemoglobin• Platelets• Absolute Neutrophil count

– Stratifies patients into 5 risk categories• Survival and AML evolution

IPSS-R Scoring System

Risk Group IPSS-R Score Median Overall Survival (years)

Median time to 25 percent AML evolution (years)

Very low <1.5 8.8 >14.5

Low >1.5 to 3.0 5.3 10.8

Intermediate >3 to 4.5 3.0 3.2

High >4.5 to 6 1.6 1.4

Very High >6 0.8 0.7

Treatment of MDS

• Asymptomatic disease: watch and wait– When patients develop transfusion*

requirement or recurrent infections, this may herald the need for treatment

Treatment of MDS

• Clinical trials• Supportive care, antibiotics, and

transfusions• Low intensity chemotherapy

– Hematopoietic growth factors, azacitidine, decitabine

• May improve QOL, but not curative

• High intensity therapy– Combination chemotherapy and HCT

Treatment of MDS

• Most treatment regimens continue until disease progression– Disease progression demonstrated by

• Worsening cytopenias• Increase in the percentage of bone marrow

blasts• Progression to a more advanced MDS FAB

subtype

MDS Coding Tips

• Keep the initial diagnostic code of MDS once established– If transformation to AML occurs, this is a

new primary

• Often transfusions and growth factors are initial forms of treatment– Neither of these are currently coded for

MDS

Therapy Related Myeloid Neoplasm (9920/3)

• Occurs after treatment – Chemotherapy, radiation, stem cell

transplant or bone marrow transplant,

• Peripheral blood and bone marrow are principle sites

• May present as either t-MDS or t-AML– WHO has one group– Must have MD statement

MULTIPLE MYELOMA: PLASMA CELL MYELOMA

Multiple Myeloma

Disease characteristic Clinical manifestation

Neoplastic proliferation of plasma cells in bone marrow

Bone pain; anemia, hypercalcemia; pathologic fractures

Plasma cell production of monoclonal immunoglobulin

Increased total serum and/or urine concentration of M protein

Plasma cell infiltration of organs; organ damage from immunoglobulin light chains

Kidney damage

Multiple Myeloma: Epidemiology

Race African Americans: Caucasian 2 to 3 times higher

Gender Slightly more frequent in men than women

Age Average age at diagnosis: 66

Diagnostic Criteria

• Clonal bone marrow plasma cells > 10%• Or biopsy proven bony or soft tissue

plasmacytoma• PLUS one of the following:

– Presence of related organ or tissue impairment:• Increased Calcium level• Renal insufficiency• Anemia• Bone lesions

– Presence of a biomarker associated with end-organ damage

Symptoms of MM

Symptom Cause

Calcium levels increase (hypercalcemia)

Product of osteoclast activating factors

Renal dysfunction Damage from light chain infiltration; M globulin infiltration and damage to kidney

Anemia Secondary to bone marrow replacement of normal hematopoeitic tissue by tumor and disruption of bone marrow microenvironment

Bone lesions, osteolytic The hallmark sign of MM; due to increased osteoclast activity with suppression of osteoblasts

Diagnosis

• Laboratory Testing– Protein electrophoresis of serum (SPEP)– Protein electrophoresis of aliquot of

urine (UPEP)– Serum free light chain assay (FLC) – Urinalysis

• Myeloma cast uropathy

– Peripheral smear– Bone marrow exam

• IHC, cytogenetics, free light chain assay

Diagnosis

• Radiographic Studies– Plain radiographs of the humeri and

femoral bones• Key component to pt evaluation

– CT, MRI and PET/CT scan– Bone scan is not a preferred method of

evaluation

Related Conditions

• MGUS• Smoldering MM*• Non-secretory MM*• Plasma cell leukemia*• Solitary plasmacytoma• Solitary extramedullary

plasmacytoma

Staging MM

• Durie-Salmon Staging – M-protein levels– Calcium levels– Bone damage– Hemoglobin

• International Staging System– Beta-2 microglobulin– Serum albumin

Transplant Eligibility

• Patients are considered ineligible for one of the following– Age > 77– Bilirubin >2.0 mg/dL– ECOG performance status 3 or 4– New York Heart Association functional

status Class III or IV

Treatment for MM

High RiskIntermediat

e RiskStandard

Risk

4 cycles of VRd or VCd

Assess Response/collec

t Stem cells

Autologous HCT if eligible

Bortezomib-based

maintenance

4 cycles of VCd

Autologous HCT if eligible

Bortezomib-based

maintenance

Eligible for transplant?

Yes No

4 cycles of Rd or VCd

Autologous HCT

Lenolidomide--based

maintenance

Rd until progressi

on

Rajkumar, S. Overview of the management of multiple myeloma. In:

UpToDate, Post TW (Ed) UpToDate, Waltham, MA (accessed 2/12/15.)

Multiple Myeloma Coding Tips

• Dexamethasone is often part of the induction therapy

• Maintenance therapy can go on for an extended period of time – Maintenance would not be considered

subsequent treatment if it was planned

Summary

• Coding histology should be as specific as possible for all these patients– Often a final diagnosis takes many weeks

• Treatment for many hematologic malignancies can span a year or more– Treatment should be considered subsequent

if it has not been considered as part of the initial treatment plan

– Treatment would be considered subsequent if the patient showed signs of disease progression

How can you become an expert in abstracting any

kind of bone marrow cancer?

http://seer.cancer.gov/seertools/hemelymph/

http://seer.cancer.gov/seertools/hemelymph/

http://seer.cancer.gov/seertools/hemelymph/

http://seer.cancer.gov/seertools/hemelymph/

AML, NOS, 9861/3

AML with inv (16)(p13.1q22) 9871/3

http://seer.cancer.gov/seertools/hemelymph/

“Any fool can know. The point is to understand.”

Albert Einstein

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SEER.

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