La anemia en los síndromes mielodisplásicos (SMD)

Guillermo SanzHospital Universitario y Politécnico La Fe, Valencia, Spain

• Introduction

• Importance of anemia

• Prognostic stratification

• Treatment of anemia

• Lower-risk patients

• Higher-risk patients

Contents of the talk

• Heterogeneous group of clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis, leading to cytopenia(s) in the presence of hypercellular bone marrow and morphological dysplasia, and high propensity to evolve to AML

• 3 – 5 cases per 100,000 population per year

• Affects primarily elderly people (median age, 75 yr)

• Clinical course very variable (few weeks to many years)

• HSC transplantation only proven curative treatment alternative

Myelodysplastic syndromes

WHO classification 2008

• Refractory cytopenia with unilineage dysplasia

• Refractory anemia with ring sideroblasts

• Refractory cytopenia with multilineage dysplasia +/- ring sideroblasts

• Refractory anemia with excess blasts (RAEB-1, 5-9%; RAEB-2, ≥10%)

• MDS-unclassified

• MDS with isolated del(5q)Cazzola et al., Hematol Clin Oncol North Am 2010

Clonal diversity of recurrently mutated genes in MDS

Walter M, et al. Leukemia 2013

Targeted seq 94 genes in 157 MDS or sAML

Distinct differences between MDS and AML

Importance of anemia in MDS

• High incidence at diagnosis, greater during evolution– Anemia symptoms at diagnosis: 50% - 70% of patients

– Hb < 10 g/dL at diagnosis: 50% - 80% of patients

• Clinical relevance – Cardiac remodeling and increased incidence of heart

failure

– Iron overload due to chronic RBC transfusions

– Poorer quality of life

– Shorter survival

• Most frequent cause for starting treatment in lower-risk patients

Greenberg PL, et al. Blood 2012; 120: 2454-2465. Malcovati L et al. Haematologica. 2011;96:1433-40.

Malcovati L. J Clin Oncol. 2005;23:7594-603. Oliva EN, et al. Leuk Res. 2005;29:1217-9.

Greenberg PL, et al. Blood. 1997;89:2079-88. Sanz GF, et al. Blood. 1989;74:395-408.

Effect of anemia on survival in MDS

Cazzola M & Malcovati L. N Engl J Med 2005;352:536-8

Transfusion dependence decreases survival rates

Overall survival1

(N = 467; HR = 1.91; p < 0.001)

Cu

mu

lati

ve p

rop

ort

ion

su

rviv

ing

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180

Survival time (months)

Transfusion-independent

Transfusion-dependent

HR = hazard ratio; pRBC = packed red blood cells.

Overall survival2

(HR = 1.36; p < 0.001)

Cu

mu

lati

ve s

urv

ival

Survival time (months)

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 20 40 60 80 100 120 140 160 180

0 U pRBC/4 weeks

1 U pRBC/4 weeks

2 U pRBC/4 weeks

3 U pRBC/4 weeks

4 U pRBC/4 weeks

1. Updated data from Malcovati L, et al. J Clin Oncol. 2005;23:7594-603.2. Updated data from Malcovati L, et al. Haematologica. 2006;91:1588-90.

Survival and AML risk by WPSS

Overall survival

(P<.001)

Risk of AML evolution

(P<.001)

Malcovati L, et al. J Clin Oncol 2007;25:3503-10

Risk of non-leukemic death by degree of anemia in MDS and gender

Malcovati L, et al. Haematologica. 2011;96:1433-40

Males Females

Risk of developing cardiac disease and death by degree of anemia in MDS

Malcovati L et al. Haematologica. 2011;96:1433-40

Hb level RBC transfusion dependency

P < 0.001 P < 0.001

Impact on survival and AML risk of RBC transfusion dependency in MDS patients (US Medicare)

Goldberg SL et al. J Clin Oncol. 2010;28:2847-52

RBC transfusion-dependent patients had a higher prevalence of different complications

Impact on survival and AML risk of RBC transfusion dependency in MDS patients (US Medicare)

Goldberg SL et al. J Clin Oncol. 2010;28:2847-52

RBC transfusion-dependent patients experienced shorter OS and higher risk of AML

Overall survival of RBC transfusion-dependent and non-transfusion-dependent patients

(European LeukemiaNet)

Significantly greater

mortality was noted in

RBC transfusion-

dependent patients.

Adapted from de Swart L, et al. Blood. 2011;118:[abstract 2775].

0

0.50

1.00

0 6 12 18

p < 0.0001

Su

rviv

al

Time (months)

0.75

0.25No

Yes

High serum ferritin is associated with worse overall and AML-free survival in MDS

Serum ferritin

< 1,000 µg/L

Serum ferritin

> 1,000 µg/Lp < 0.0001

Serum ferritin

< 1,000 µg/L

Serum ferritin

> 1,000 µg/L

p < 0.0001

Overall survival

by serum ferritin level

(n = 762)

AML-free survival

by serum ferritin level

(n = 761)

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20

Years from diagnosis

Pro

ba

bil

ity

0.0

0.2

0.4

0.6

0.8

1.0

0 5 10 15 20

Years from diagnosis

Pro

ba

bil

ity

Sanz G, et al. Blood. 2008;112:[abstract 640].

Quality of life is associated with hemoglobin level in cancer patients

Hb level (g/dL)

Qu

ality

of

life

/LA

SA

sco

re (

mm

)

45

50

55

60

65

7 8 9 10 11 12 13 14

Crawford J, et al. Cancer. 2002;95:888-95.

0,0

0,2

0,4

0,6

0,8

1,0

1,2

1,4

Prestudy Week 1-15 Week 16-17 Week 18-26

Un

its

/pa

tie

nt/

we

ek

Darbepoetin treatment, CR at week 16, n=10

0,00

10,00

20,00

30,00

40,00

50,00

60,00

70,00

Fa NV Pa Dy Sd Ap Co Di Fi

Symptoms

sco

re Studystart

End of study

Transfused pts, n=19

0,00

10,00

20,00

30,00

40,00

50,00

60,00

Fa NV Pa Dy Sd Ap Co Di Fi

Symptoms

Sc

ore Studystart

End of study

Nilsson-Ehle H et al. Eur J Haematol. 2011;87:244-52

Anemia and quality of life in MDS patients(Nordic MDS study Group)

• Darbepoetin G-CSF to achieve a hemoglobin target of 12 g/dL at week 16. Complete responders continue treatment until week 26. Non-responders received RBC transfusions to achieve that target.

• Quality of life (QOL) was assessed at week 26.

DBP complete responders (n = 10) Transfused patients (n = 19)

Great prognostic heterogeneity

Advanced age

Comorbidity and associated diseases frequent

Curative modalities (i.e. allo-HSCT): high morbidity and mortality

Treatment of MDS: General principle

Risk-adapted treatment essential

IPSS-R: Prognostic score values

Variable Category, points

Cytogenetics*

Very Good

0Good

1Intermediate

2Poor

3

Very Poor

4

BM blast, % ≤20

>2 and <51

5 - 102

>103

Hb, g/dL ≥100

8 - <101

<81.5

ANC, x 109/L >0.80

≤0.80.5

Platelets, x 109/L ≥1000

50 - <1000.5

<501

*As defined by Schanz J et al. J Clin Oncol 2012; 30: 820-829.

Greenberg PL, et al. Blood 2012; 120: 2454-2465.

IPSS-R: Risk groups and scores

Greenberg PL, et al. Blood 2012; 120: 2454-2465.

Risk group Score (points)

Very low 0 – 1.5

Low 2 – 3

Intermediate 3.5 – 4.5

High 5 – 6

Very-high > 6

Months Months

Greenberg PL, et al. Blood 2012; 120: 2454-2465.

• Improved predictive power and validated in external series but more complex

Survival AML-free survival

Risk-adapted treatment of MDS

Prognostic scoring systems: IPSS-R

Risk-adapted treatment of MDSRisk groups in clinical practice

Treatment approaches are limited

Two risk groups recognized in daily practice

Lower-risk

Higher-risk

Advantage: Symptomatic anemia only reason for treatment remaining in patients with lower-risk MDS

Risk-adapted treatment of MDSGESMD definition of higher risk patients

IPSS-R high or very high

IPSS int-1 with one or more of the following features

High or very high risk cytogenetics (by IPSS-R)

Severe neutropenia (< 0.5 109 PMN/L)

Severe thrombocytopenia (< 30 109 platelets/L)

Moderate/severe BM fibrosis (grade 2 – 3)

Sanz G et al. Haematologica (Spanish ed.) 2012; 97 (suppl 5): 1 – 58.

Treatment modalities for MDSGoals of treatment and candidates for

active treatment Lower-risk patients

Goal: Improve symptoms and quality of life

Candidates: Symptomatic cytopenia/s (anemia) present. A watchful waiting strategy requires careful monitoring

Higher-risk patients

Goal: Modify natural history of the disease and improve survival

Candidates: All patients. Avoid delay

Treatment modalities for MDSBest supportive care

Best supportive care (BSC) remains essential for the appropriate management of every single patient with MDS

BSC includes:

RBC transfusions

Platelet transfusions

Antimicrobial therapy

Iron chelation

Symptomatic

anemia

Probability

to respond

to ESAs

Clinical changes

or progression

Yes

No

Watchful

waiting

strategy

Low

Intermediate

or high

Close monitoring

No

Re-evaluate strategy

BSC or

Clinical trial or

Second-line approaches

in patients failing or

losing response:

- AZA

- ATG

- Allo-HSCT

- lenalidomide

Yes

del(5q)

Positive

Failure or

loss of response

Negative

ESAs

G-GSFLenalidomide

Failure or

loss of response

Therapeutic algorithm for lower-risk MDS patients (GESMD)

Treatment modalities for MDSErythopoiesis stimulating agents (ESAs) (1)

ESAs are considered first-line treatment for symptomatic anemia of lower-risk MDS patients.

Erythroid response rate (IWG criteria) 20 – 70%

Median response duration: 18 – 24 months

No effect on AML risk

No increase risk of DVT reported

Potential survival benefit (especially in patients with low transfusion requirements and responders)

Impact of EPO + G-CSF on overall survival of MDS patients(Nordic MDS Study Group and University of Pavia)

Jädersten M et al. J Clin Oncol 2008; 26:3607-13

Overall series < 2 pRBC/month

Treatment modalities for MDSErythopoiesis stimulating agents (ESAs) (2)

Responses usually seen in first 12 weeks

A dose effect seems to be present

Darbepoetin and epoetin seem to give similar responses at equipotent doses

A substantial proportion of patients failing ESAs (16 – 50%) respond to the addition of G-CSF

Endogenous serum EPO level and RBC transfusion requirements are strongly associated with likelihood and duration of response (Nordic MDS Study group model)

Treatment guidelines for use of ESAs in MDS

ESAs should be used according to the Nordic MDS study group predictive model of response.1,2

Use of ESAs in patients with both pejorative criteria (≥ 2 RBC units per month and EPO endogenous level ≥ 500 UI/L) is not recommended.

Variable 0 points 1 point

RBC transfusion requirements

< 2 units/month ≥ 2 units/month

Serum EPO level < 500 U/L ≥ 500 U/L

Score Response rate Response duration

0 74% 24 months

1 23% 23 months

2 7% 3 months

1 Hellstrom-Lindberg E et al. Br J Haematol 2003:120:1037-46.2 Jadersten M, et al. Blood 2005; 106 (3): 803-11

The 5q- syndrome

• 3-4% of all MDS

• Female preponderance

• Macrocytic anemia

• Thrombocytosis

• Hypolobated megakaryocytes

• Isolated interstitial deletion of 5q

• Indolent course (?)

Van den Berghe. Nature 1974; Schanz et al, JCO 2011

Treatment modalities for MDSLenalidomide in lower risk MDS with del(5q) and

RBC transfusion dependence

MDS with del(5q) are specially sensitive to lenalidomide

RBC transfusion independence (RBC-TI): 43 – 67%

Cytogenetic response: 25 – 73% (complete, 16 – 45%)

Median duration of RBC-TI > 2 years

RBC-TI higher with 10 mg/d x 21 – 28 d than with 5 mg/d

Most common grade 3 -4 adverse events

Neutropenia: 55 – 75%

Thrombocytopenia: 33 – 44%

Treatment modalities for MDSLong-term outcome after lenalidomide in lower risk MDS with del(5q) and RBC transfusion dependence

Potential benefit in overall survival for responders

Fenaux P, et al. Blood 2011; 118: 3765-3776.

Treatment modalities for MDSLong-term outcome after lenalidomide in lower risk MDS with del(5q) and RBC transfusion dependence

Three retrospective comparative studies using different methodology have not shown any significant effect on AML risk

Ades L, et al. Haematologica 2012; 97: 213-218.Kuendgen A, et al. Leukemia 2013: 27(5):1072-1079.

Sánchez-García J, et al. (sumbitted)

LEN

No LEN

Candidate to

Intensive

treatment

Cytogenetics

Donor

Donor

Yes

No

HLA typing

Donor search

High-risk

Low-risk

BM blastsYes

No

Allo-HSCT or

AZA followed by allo-HSCT or

CT followed by allo-HSCT

AZA followed by allo-HSCT or

CT followed by allo-HSCT

≤ 10%

> 10%

AZACT or

Clinical trial

Failure

BM blastsYes

No

Allo-HSCT≤ 10%

> 10%

CT or

AZA

Allo-HSCT or

AZA followed by allo-HSCT or

CT followed by allo-HSCT

AZA

Therapeutic algorithm for higher-risk MDS patients (GESMD)

Treatment modalities for MDSHypomethylating drugs: azacitidine

Fenaux P, et al. Lancet Oncol 2009;10:223-232

Log-Rank p=0.0001

HR = 0.58 [95% CI: 0.43, 0.77]

0 5 10 15 20 25 30 35 40

Time (months) from Randomization

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

po

rtio

n S

urv

ivin

g

CCRAZA

Difference: 9.4 months

24.4 months

15 months

50.8%

26.2%

Treatment modalities for MDSHypomethylating drugs

Azacitidine should be considered as first-line treatment in higher-risk MDS not considered candidates for intensive treatment.

Azacitidine should also be considered as first-line treatment in higher-risk patients who are candidates to intensive treatment but lack an appropriate donor for allo-SCT (preferable to AML chemotherapy in patients aged over 65 years or with comorbidity, and in those presenting high-risk cytogenetics)

Treatment modalities for MDSAML-type chemotherapy

Long term results

5 – 10%

• Patients with higher probability of long-term DFS (30%):

• Age < 60 yr

• No comorbidity

• Favorable cytogenetics

Kantarjian H, et al. Cancer 2006; 106:1099-1109.

Candidates

Treatment modalities for MDSAllogeneic SCT

Allo-SCT is the only proven curative modality for MDS and should be considered as first-line treatment in higher-risk MDS considered candidates for intensive treatment.

Results have improved despite greater use of MUD transplants and older patient age

Key questions under debate

Access to transplant has increased but still limited to a minority of MDS patients ( 10%)

Anemia has great relevance in MDS

Despite great advances in the last decade, treatment remains largely unsatisfactory

Until more targeted, active, and less toxic therapies become available risk-adapted treatment will continue to be essential

Patients must be included in clinical trials whenever possible

Final comments