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©2012 MFMER

Evaluation of IPSS-Revised (IPSS-R) Cytogenetic Risk Stratification and Prognostic Impact of Monosomal Karyotype in 1,014 Patients with Myelodysplastic Syndromes (MDS)Naseema Gangat, Mrinal M. Patnaik, Kebede Begna, Taxiarchis Kourelis, Ryan A Knudson, Rhett P Ketterling, Janice M Hodnefield, Curtis A Hanson, Animesh Pardanani, and Ayalew Tefferi

American Society of HematologyDec 10th 2012

©2012 MFMER | slide 2

Introduction

• Cytogenetic abnormalities at diagnosis occur in 20-70% of patients with myelodysplastic syndromes (MDS)

• International Prognostic Scoring System -revised (IPSS-R) classifies these abnormalities into five prognostic groups


IPSS-RCytogenetic categories

Very good Good Intermediate Poor Very Poor

-Y Normal del(7q) -7 Complex: > 3

abnormalities

del(11q) del(5q) +8 inv(3)/t(3q)/del(3q)

del(20q) +19 Double including -7/del(7q)

del(12p) i(17q) Complex: 3 abnormalities

double including del(5q)

other single/ double

independent clones Schanz, J, JCO 2012


ObjectivesI and II

• Validate the IPSS-R cytogenetic categories in an independent cohort of patients with MDS

• Evaluate the prognostic impact of monosomal karyotype (MK)


Patient CohortN=1,014

(783)

(231)


Patient DemographicsClinical characteristics (N=783)

Variables Value

Age > 60 years, N(%) 662(85)

Hemoglobin < 10 g/dl, N(%) 444(57)

Platelets < 100 x 109/L, N(%) 369(47)

Bone marrow blast %, median (range) 2(0-19)

Followup in months, median (range) 22(0-222)

Deaths, N(%) 562(72)

Leukemic transformation, N(%) 92(12)


Patient CohortWHO Classification (N=783)

%

Text

Text

Text


IPSS-R Cytogenetic Categories (N=783)


IPSS-R (Age-adjusted)Primary MDS (N=783)

%

Greenberg, P, Blood 2012


Survival by IPSS-R karyotypePrimary MDS (N=783)

Survival

Time

● Good (n=492), median survival 40 months

∆ Very good (n=43), median survival 21 months

○ Intermediate (n=139), median survival 24 months

▲ Poor (n=32), median survival 18 months

▼ Very poor (n=77), median survival 6.5 months

P <0.0001


Survival by IPSS-R karyotypePrimary MDS (N=783)

Survival

Time

▲Very good (n=43), median survival 21 months

● Intermediate (n=139), median survival 24 months

○ Poor (n=32), median survival 18 months

P=0.79


Multivariable analysisPrimary MDS (N=783)

Hazard ratio

95% Lower CI 95% Upper CI P value

IPSS-R karyotype Very goodVery poorPoorIntermediateGood

2.41.11.00.7

1.50.60.70.5

3.71.91.61.0

0.00020.750.890.07

Age > 60 years 1.8 1.4 2.4 <0.0001

Hemoglobin < 10 g/dl 1.3 1.1 1.6 0.0007

Platelets <100 x 109/L 1.3 1.1 1.5 0.01

Bone marrow blast % 1.1 1.04 1.08 <0.0001


IPSS-R karyotypeGood vs Very good (N=535)

Survival

Time

● Good (n=492), median survival 40 months

○ Very Good (n=43), median survival 21 months

P=0.05


IPSS-R karyotypeGood vs Very good (N=535)

Time

Survival

○ Good del(5q) (n=81), median survival 53 months

● Good normal (n=375), median survival 39 months

▼Good del(20q) (n=35), median survival 28 months

Very good –Y (n=32), median survival 22 months

▼Very good del(11q) (n=11), median survival 20 months

∆ Good del(12p) (n=1), median survival 16 months

P=0.12


Multivariable analysisVery Good vs Good (N=535)

Hazard ratio

95% Lower CI 95% Upper CI P-value

IPSS-R karyotype Very good –Y

Good normalGood del(5q)Good del(20q)Good del(12p)Very good del(11q)

0.80.60.92.31.3

0.50.40.50.30.6

1.21.01.6173.1

0.240.050.770.420.51

Age 1.02 1.01 1.03 0.0001


Conclusions I

• IPSS-R cytogenetic categories failed to discriminate between very good, good, intermediate and poor prognostic groups

• Very Good has a worse prognosis than Good del(5q) and normal karyotype


IntroductionMonosomal karyotype (MK)

• Presence of two or more autosomal monosomies or a single monosomy associated with a structural abnormality

• Prognostically worse subgroup of patients with complex karyotype

inv(3)(q21q26) and monosomy 7 Patnaik M, Leukemia 2010


IPSS-R karyotypeMonosomal karyotype (MK)

Survival

Time

● Poor without MK (n=24), median survival 19 months

▲Poor with MK (n=8), median survival 15 months

○ Very poor without MK (n=13), median survival 9 months

∆ Very poor with MK (n=64), median survival 5 months

P=0.0004


IPSS-R karyotypePoor with and without MK (N=32)

Survival

Time

● Poor without MK (n=24), median survival 19 months

○ Poor with MK (n=8), median survival 15 months

P=0.23


IPSS-R karyotypeVery poor with and without MK (N=77)

Survival

Time

● Very poor without MK (n=13), median survival 9 months

○ Very Poor with MK (n=64), median survival 5 months

P=0.048


IPSS-R karyotypePoor, Very poor with and without MK (N=109)

Survival

Time

● Poor (n=24), median survival 19 months

○ Very Poor (n=13), median survival 9 months

▲MK (n=72), median survival 6.5 months

P=0.001


Multivariable analysisMonosomal karyotype (N=72)

Hazard ratio

95% Lower CI 95% Upper CI P-value

Very poor with MK

Poor without MK 0.35 0.19 0.61 0.0002

Very poor without MK 0.48 0.24 0.95 0.034

Poor with MK 0.53 0.25 1.13 0.099


Conclusions II

• The presence of MK warrants inclusion into the very poor risk category


Next

• Revised cytogenetic classification


Revised IPSS-RCytogenetic categories

Very good Good Intermediate Poor Very Poor

del(5q) Normal -Y Poor without MK MK

del(11q) Very poor without MK

del(20q)

del(12p)

Intermediate


Survival by karyotypeRevised Very Good, Good, Intermediate

Survival

Time

● Very good (del(5q) (n=81), median survival 53 months

○ Good (normal) (n=375), median survival 39 months

▲ Intermediate (-Y, del(11q), del(20q), del(12p)(n=79), median survival 26 months

P=0.045


Survival by karyotypeRevised Poor and Very poor

Survival

Time

● Poor (Poor, very poor without MK)(n=37), median survival 15 months

○ Very poor (MK) (n=72), median survival 6.5 months

P=0.0002


Survival by karyotypePrimary MDS (N=783)

Survival

Time

▼ Very Good (n=81), median survival 53 months

∆ Good (n=375), median survival 39 months

▲ Intermediate (n=218), median survival 25 months○ Poor (n=37), median survival 15 months

● Very poor (n=72), median survival 6.5 months

P<0.0001


Multivariable analysisCox proportional hazards (N=783)

Hazard ratio


IPSS-R karyotype Very goodVery poorPoorIntermediateGood

5.21.51.71.2

3.50.961.20.88

7.72.52.31.6

<0.00010.070.00120.26

Age > 60 years 1.9 1.5 2.6 <0.0001

Hemoglobin < 10 g/dl 1.4 1.2 1.7 <0.0001

Platelets <100 x 109/L 1.2 1.02 1.5 0.02



Survival by karyotypePrimary MDS (N=783)

Survival

Time

▲ Low (de(5q), normal) (n=456), median survival 42 months○ Intermediate (-Y, del(11q), del(20q), del(12p), int, poor, very poor without MK) (n=255), median survival 22 months

● High (MK) (n=72), median survival 6.5 months

P<0.0001


Multivariable analysisCox proportional hazards (N=783)

Hazard ratio


IPSS-R karyotype LowHighIntermediate

4.51.4

3.31.2

6.11.7

<0.00010.0001

Age > 60 years 2.0 1.5 2.6 <0.0001

Hemoglobin < 10 g/dl 1.4 1.2 1.7 <0.0001

Platelets <100 x 109/L 1.2 1.03 1.5 0.02


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