Overview of Myelodysplasia and New Harmonized CIBMTR Forms

Corey Cutler, MD MPH FRCPCAssistant Professor of Medicine

Harvard Medical SchoolDana-Farber Cancer Institute

Hematopoiesis

Hematopoiesis – the process by which blood cells are madePluripotent Hematopoietic Stem Cell – able to develop into any type of blood cell

Primary Myelodysplastic Syndromes

A group of hematopoietic disorders sharing an ineffective production of one or more myeloid cell lines

Ineffective hematopoiesis : Anemia, Thrombocytopenia and Neutropenia

Dysplastic hematopoiesis: Recurrent cytogenetic abnormalities arising from dysplastic clones

MDS encompasses several different, but related, conditions and in some instances may be mistaken for aplastic anemia or a myeloproliferativedisease

Median age is 70 and 30% progress to AML

Leukemia Stats: 2004/USA

Cell Type Child Adult Total AML 1,000 9,400 10,400 ALL 3,000 1,300 4,300 CML 120 4,400 4,520 CLL - 11,000 11,000 MDS 1,000 12,000 13,000 Totals 5,120 38,100 43,220

MDS Prevalence: 35 000 – 55 000 cases in USA

Age-Related Incidence of MDS

0 0 2 1 2 2 49

16

26

5259 61

34

10

10

10

20

30

40

50

60

70

20- 25- 30- 35- 40- 45- 50- 55- 60- 65- 70- 75- 80- 85- 90- 95-

Williamson PJ, et al. Br J Haematol. 1994 Aug;87(4):743-5.

Age

Age-specific incidence rates (per 100,000)

Less than 50 0.550-59 5.360-69 1570-79 4980 and over 89

Presenting Symptoms

Easy bruisability and bleeding, Spontaneous hemorrhage when severe.Thrombocytopenia

Susceptibility to infections increased; recurrent feversNeutropenia

Pallor, severe fatigue, shortness of breath; angina or heart attack

Severe anemia: Hct < 25%

Some fatigue, palpitations, shortness of breath, pallor

Mod. anemia: Hct 25-30%

Normal or slightly fatiguedMild anemia: Hct 30–35%

Anemia

• Patients with MDS present with signs and symptoms of bone marrowfailure –anemia, neutropenia and thrombocytopenia

• Nearly half of all patients with MDS may have no symptoms at all• Abnormal blood counts are noted on routine examination

Predisposition

Acquired:SenescenceMutagen/Genotoxic Stress

Therapeutic alkylators, Topo-II agents, β-emitters (32P), autoSCTEnvironmental/occupational (herbicides; pesticides; heavy petrochemical exposure) NQ01 polymorphismsTobacco

Aplastic anemiaPNH

List AF, et al. The Myelodysplastic Syndromes. In: Wintrobe’s Hematology 2003.

Heritable:Constitutional genetic disorders

Trisomy 8 mosaicismFamilial monosomy 7

Neurofibromatosis 1Embryonal dysgenesis (del12p)Congenital Neutropenia

Kostmann, Schwachman-DiamondDNA repair deficiencies

Fanconi anemia, AT, Bloom syndrome

Pharmacogenomic polymorphisms (GSTq1-null)

Exposures

Alkylating agentsRadiation

Long Latency80% with–5 (del 5) and/or MDS/AML–7 (del 7) + othersdel (3p), del (17p)

Topoisomerase II t(8;21)

(Etoposides, anthracyclines)t(15;17)

AML1 gene (21q22)

q11ALL (MLL genes)11q23

Short Latency

•Morphologic: FAB (1982)

•Prognostic: IPSS (1997)

•Combined (morphologic, cytogenetic and prognostic): WHO (2001)

Classification of MDS

Acute myeloid leukemia (AML)RAEB in transformation (RAEB-t)

WHOFAB

Refractory anemia with excess blasts -1 (RAEB-1)Refractory anemia with excess blasts-2 (RAEB-2)

Refractory anemia with excess blasts (RAEB)

Refractory anemia with ringed sideroblasts (RARS)Refractory cytopenias with multilineagedysplasia & ringed sideroblasts (RCMD-RS)

Refractory anemia with ringed sideroblasts (RARS)

Refractory anemia (RA)Refractory cytopenias with multilineagedysplasia (RCMD) MDS-unclassified (MDS-U)MDS with isolated del(5q)

Refractory anemia (RA)

FAB vs WHO

WHO Classification of MDS - Modifications

t(8;21) - AML1/ETO

t(15;17) - PML/RARα

inv(16) or t(16;16) -CBFβ/MYH11

11q23 (MLL)

Reclassification:

CMML MPD

RAEB-t

Irrespective of % Blasts are considered as AML:

Acute myeloidleukemia withmultilineagedysplasia

PNH

AA

CMML

aCML

MDS-AMLRA

RAEB

RARS

hypo-plasticMDS

de novo AML

CGL

RAEB-t

t-AML

MDS/MPD/AA

BONE MARROW BIOPSY:

Markedly hypercellular marrow (5% fat).Approximately 10-15% of the cellularity is comprised of intermediate sizedmononuclear cells with round nuclei, dispersed chromatin, distinct prominentnucleoli, consistent with blast forms as confirmed by immunoperoxidase studiesperformed on paraffin sections for CD34.Erythroid elements are mildly proportionally increased, exhibit maturation andinclude increased number of early forms.Myeloid elements are mildly proportionally decreased, exhibit maturation andinclude an increased number of early forms.Megakaryocytes are present in normal numbers and include occasional smallhypolobated forms.Scattered lymphocytes and plasma cells are seen.Bone trabeculae exhibit focal osteoblastic activity.Giemsa stain examined for final diagnosis of bone marrow biopsy.The aspirate smear findings are of a markedly hypercellular, spicular smearshowing maturing trilineage hematopoiesis, increased numbers of blasts,moderate dyserythropoiesis, and mild dysmyelopoiesis. Myeloid and erythroidelements are markedly left-shifted. Marked erythroid hyperplasia is present.

Overall, the findings are consistent with persistent involvement by thepatient's MYELODYSPLASTIC SYNDROME, best characterized as refractory anemiawith excess blasts (RAEB-2).

KARYOTYPE: 44,XY,add(3)(p11),del(5)(q14),-7,inv(9)(p12q13),psudic(12)t(12;18) (p12-13;p12),der(16)t(3;16)(p11;q24)[cp12]/46,idem,-3,del(22)(q22),+2mar[cp8]

METAPHASES COUNTED: 20 ANALYZED: 10 SCORED: 10 BANDING: GTG

INTERPRETATION:All metaphases contained the clonal aberrations described above, includingdeletions of 5q and monosomy 7. Both these aberrations are characteristicfindings in MDS or AML. Similar aberrations were observed in a previous bonemarrow specimen from this patient, and here are consistent withpersistent/recurrent MDS or AML.

X

XXX

+3,inv(9),der(16)t(3;16)(p11;q24), -3

KARYOTYPE: 44,XY,add(3)(p11), del(5)(q14), -7, inv(9)(p12q13), psudic(12) t(12;18) (p12-13;p12), der(16)t(3;16)(p11;q24)[cp12]/46,idem,-3,del(22)(q22),+2mar[cp8]

X

*Good = normal, -Y, del(5q), del(20q); Intermediate = other karyotypic abnormalities; Poor = complex (≥3 abnormalities) or chromosome 7 abnormalities

**Hb <10 g/dL; ANC <1800/μL; platelet count <100,000/μL

Greenberg PL et al. Blood. 1997;89:2079

IPSS: International Prognostic Scoring System

All 3 prognostic variables required to generate IPSS score

Prognostic Variable 0 0.5 1 1.5 2

Bone marrow blasts (%) <5 5–10 - 11–20 21–30

Karyotype* Good Intermediate Poor -

Number of cytopenias** 0/1 2/3 - - -

Score Value

Risk Group: Low Int-1 Int-2 HighScore: 0 0.5-1.0 1.5–2.0 ≥2.5

Low Risk 31%

Int-1 Risk 39%

Int-2 Risk 22%

High8%

Greenberg PL et al. Blood. 1997;89:2079

IPSS Risk Categories Distribution

IPSS

1 2Years

100

90

80

70

60

50

40

30

20

10

00 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Perc

ent

A

Survival (<60 years old) Survival (≥60 years old)

1 2Years

100

90

80

70

60

50

40

30

20

10

00 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

Perc

ent

BLow 60 ptsInt-1 87 ptsInt-2 49 ptsHigh 9 pts

Low 207 pts

Int-2 127 ptsHigh 50 pts

Int-1 227 pts

Source: Bennet, John M. MDS: Past, Present, Future. Presentation

Source: Bennet, John M. MDS: Past, Present, Future. Presentation

WHO MDS Subtypes5q- 3%

PRA8%RAEB-2

18%

RAEB-1 21%

PRA11%

RCMD 24%

RSAMD15%

Survival (months)

RAEB-2, 10

5q- , 116

RAEB-1 , 18

RSAMD, 32

PRA, 69

RCMD , 33

PSA, 69

Survival and WHO Subtypes

Therapy of MDS

Considerations:• IPSS, WHO/FAB Classification• Age / Performance Status• HLA-DR• Cytogenetics

Options:• General supportive care including transfusion, antibiotics• Cytokines – Erythropoeitin/G-CSF/Androgens• Immunosuppressive therapy: ATG, Steroids, Cyclosporine/FK506 • Single agent chemotherapy: Busulfan, Hydrea, Cytarabine• Multiple agents +/- BMT• Novel new drugs

• Hypomethylating agents (Dacogen, Vidaza)• IMIDs (Thalidomide, Revlimid)

IWG Response Criteria in MDS

Cheson BD, et al. Blood 2000. 96:3671-4.

RBC (HI-E): Major: Treatment-indepen. or >2g/dl ↑ in Hgb; Minor: 50% ↓ in tx req or 1-2 g/dl ↑ in Hgb.PLT (HI-P):Major: PLT tx indep or ↑ by 30K if < than 100K at baseline;Minor: 50% ↑ in PLT count (of at least 10K) if baseline <100K.PMN (HI-N):Major: if ANC <1500, a 100% ↑ or 500/ μl, ↑ whichever greater; Minor: if ANC <1500, ANC ↑ by 100%, but < than 500/ μl.

HematologicImprovement

Same as CR; ↓ blasts by 50%Partial Remission

<5% BM blasts, No dysplasia; Hgb>11; PMN>1.5, PLT>100KComplete Remission

Transplantation for MDS

Only curative therapy available

0

500

1,000

1,500

2,000

2,500

AMLALL NHL MDS

Non-Malignant Diseases

CMLCLL Myeloma

Other Malignancies

Hodgkin's

Neuroblastoma

Tran

spla

nts

Source: CIBMTR 2005 slideset

Adapted from Deeg et al, Blood 2002

Related vs. Unrelated Donors

Castro-Malaspina et al, Blood 2002

NMDP Experience

Thanks for your attention

Good luck with the new forms!!!