The Role of ESA’s in Lymphoproliferative -...

The Role of ESA’s in Lymphoproliferative

disease

Dr Ruth Pettengell

St Georges University Hospitals Foundation

Trust

O-IHQ-AMG-619-2014-October-NP

Date of Preparation October 2014

Evaluation of Anaemia

Haemoglobin (Hb) ≤11g/dL or ≥2g/dL below baseline

Evaluate anaemia for possible cause;

Reticulocyte count and mean corpuscular volume

Hemorrhage

Haemolysis

Nutritional

Inherited

Renal dysfunction

Radiation-induced myelosuppression

Treat as indicated

Unknown etiology

Anaemia of chronic inflammation or anaemia caused by

myelosuppressive chemotherapy

NCCN Guidelines v2 2015

CBC with indices

Blood smear morphology

Treatments for the management of anaemia

Iron supplementation

• Absolute iron deficiency – IV or oral iron supplementation

• Functional iron deficiency - IV iron supplementation plus

erythropoietic therapy (ESA)

Treatments available if anaemia is not related to absolute or functional

iron deficiency.

ESAs in the cancer setting Red blood cell transfusions

Risks Increase in thrombotic events Increase in thrombotic events

Possible decreased survival Transfusion reactions

Time to tumour progression shortened Transfusion associated circulatory overload

Virus transmission, Bacterial contamination

Iron overload

Possible decreased survival

Benefits Transfusion avoidance Rapid increase of Hb and hemacrit levels

Gradual improvement in anaemia

related symptoms

Rapid improvement in anaemia related

symptoms

NCCN Guidelines v2 2015

Guidelines on ESAs in CIA

Recommendation ASCO/ASH1 NCCN2 EORTC3 ESMO4 EORTC5

When to start

Hb ≤10 g/dL(clinical

decision if Hb 10-12 g/dL)

Hb ≤11 g/dLHb 9-11 g/dL

(clinical decision if Hb ≤11.9 g/dL)

Hb ≤10 g/dL Hb ≤10 g/dL

Target range

Lowest Hb level needed

to avoid transfusions

Maintain10-12 g/dL

Symptomatic patients’ target Hb should be

around 12 g/dL

Should not exceed 12 g/dL

10-12 g/dL

Generalrecommendation

• Iron deficiency should be corrected before ESA treatment• Blood transfusions should be kept to a minimum!• Benefits of ESA therapy should be carefully weighed along

with its safety concerns when determining anemia treatment

options

1 Rizzo J, et al. Blood. 2010;116:4045-59; 2 NCCN Clinical Practice Guidelines in Oncology: Cancer- and Chemotherapy-Induced Anemia. Version 3.2014; 3 Bokemeyer C, et al. Eur J Cancer. 2007;43:258-70; 4 Schrijvers D, et al. Ann Oncol. 2010;21 Suppl 5:v244-7; 5 Aapro M, et al. In preparation.

Anaemia: Incidence and Prognostic value by

histology

Moullet et al. Ann Oncol 1998;9:1109-1115

Anaemia outcomes: CRR 53% vs 69% , PFS 15 vs 64 mo, OS 47 vs 146 mo

MVA for OS: age ≥60y, PS ≥2, anaemia, raised LDH, high b2m, liver involvement

MVA for PFS: age ≥60y, raised LDH, anaemia, BM involvement, high b2m, PS ≥2,

Anaemia: OS by histology

Moullet et al. Ann Oncol 1998;9:1109-1115

CLL

TCL DLBL

FLMZL

MCL

Response by selected cancer types

Ludwig et al. EJC 2009;45:1603-1615

Retrospective, n=2192 pts (14.8% lymphoma, If Hb< 11g/dl ESA for 8-10

wks)

Hedenus M et al. Br J Haematol. 2003 Aug;122(3):394-403.

DA in anaemic patients with Lymphoma and Myeloma

• Phase 3, 349 lymphoma or myeloma pts,

• Darbepoetin alfa 2.25 mcg/kg or placebo s.c., once weekly for 12 weeks

• Hb response defined as an increase of ≥ 2g/dl from baseline with no RBC transfusion in 28 d

• mean changes Hb from baseline in treatment(1.80 g/dl vs 0.19 g/dl) and

after 12 weeks of treatment (2.66 g/dl vs 0.69 g/dl).

• Fewer RBC transfusions in the DA group (P < 0.001)

http://www.ncbi.nlm.nih.gov/pubmed/12877666


DA in anaemic patients with LPD: FACT-Fatigue subscale



DA in anaemic patients with LPD

AE’s in ≥ 15% patients


Osterburg et al. Br J Haematol. 2005;129, 206-209.

Years from start of treatment

Overa

ll surv

ival

1 2 3

100

80

60

40

20

0

Placebo median OS 18 mo

Epoetin-β median OS 17 mo

Epoetin-β in anaemic patients with LPD : OS

343 patients, Epoetin-β 3x/w for 16 w

Hb response at 16 w (>2g/dl 67% vs 27%, p<0.0001),

Improvement QOL, FACT scale p<0.05


Anemia and ESA administration in NHL

patients treated with CHOP +/-R

• ESAs (darbepoetin alfa, epoetin alfa, or epoetin beta) according to

routine clinical practice

• Anemia was defined as Hb <10 g/dL

• 1829 patients received 1 or more cycles, 33% were anemic during CT

• 404 patients (22%) received ESA treatment

• 45% of patients had Hb <10 g/dL, 14% Hb <9 g/dL

• Of 94 patients with Hb <10 g/dL at ESA initiation, 56% (Kaplan-Meier

88%) achieved target Hb values of 10-12 g/dL

• 65% had Hb 9-11 g/dL at ESA initiation, and 89% (Kaplan-Meier

percentage) achieved Hb 10-12 g/dL

Haioun C, et al. Hematology. 18(1):26-9, 2013 Jan.

Darbepoetin alfa Epoetin alfa Epoetin beta Any ESA†

Hb <10 g/dL at ESA initiation and in study at week 5

N=89 N=37 N=33 N=159

Achieved Hb ≥10 g/dL

KM % (95% CI)95 (87, 103) 90 (73, 106) 93 (80, 106) 95 (89, 101)

Achieved Hb 10–12 g/dL

KM % (95% CI)92 (78, 105) 78 (46, 110) 81 (63, 99) 89 (78, 101)

Hb<11 g/dL at ESA initiation and in study at week 5

N=155 N=58 N=58 N=271

Achieved Hb ≥11 g/dL

KM % (95% CI)88 (74, 101) 79(60, 99) 76 (61, 91) 86 (75, 96)

Hb values within 28-days after transfusions are excluded

Achievement of target Hb from ESA start + 5 weeks to ESA completion

Mean duration ESA 8.7 ± 6.9 weeks

NHL patients treated with CHOP +/-R


Impact of ESA initiation on Hb levels baselined at the point of ESA

initiation

9

9.5

10

10.5

11

11.5

12

12.5

13

13.5

-8 -7 -6 -5 -4 -3 -2 -1 0 1 2 3 4 5 6 7 8

Cycles Pre-ESA Initiation ESA Initiation Cycles Post ESA Initiation

Me

an

Hb

(g

/dL

)

ESA initiated in cycle 1 (n=134) ESA initiated in cycle 2 (n=70) ESA initiated in cycle 3 (n=66)ESA initiated in cycle 4 (n=54) ESA initiated in cycle 5 (n=39) ESA initiated in cycle 6 (n=24)ESA initiated in cycle 7 (n=11) ESA initiated in cycle 8 (n=6)

Hb values within 28-days af ter transfusions are excluded



Timing of transfusions in patients receiving an ESA

0

5

10

15

20

25

30

35

40

45

50

% o

f A

ll T

ran

sfu

sio

ns p

er

Tre

atm

en

t G

rou

p

1-2 3-4 5-6 7-8 9-10 11-12 >12

Weeks after ESA initiation

Darbepoetin alfa Epoetin-alfa Epoetin-beta Any ESA



Odds ratio (95% CI) p-value

Predictors of anemia (Hb<10 g/dL) (1413 observations)

Age (per year) 1.03 (1.02, 1.04) <0.0001

Number of chemotherapy cycles 1.17 (1.07, 1.27) 0.0003

Baseline Hb (per 1 g/dL) 0.63 (0.58, 0.70) <0.0001

Sex (female vs. male) 1.75 (1.35, 2.27) <0.0001

Ann Arbor Stage (IV vs. I–III) 1.51 (1.15, 1.97) 0.0027

CT (CHOP-14 vs. CHOP-21) 3.38 (2.55, 4.48) <0.0001

Cell type (DLBCL vs. Non-DLBCL) 1.32 (0.99, 1.76) 0.0604

Older age, lower baseline Hb, worse performance status, advanced stage,

and intensive chemo were significant predictors of transfusion and anemia

NHL patients treated with CHOP +/-R :

predictors of anemia


Hemoglobin (Hb) levels over time.

Andreas Engert et al. JCO 2010;28:2239-2245

Advanced Hodgkin Lymphoma:GHSG HD15 EPO Trial

(N=655)

(N=648)

BEACOPP ± Epoetin alfa 40,000 U weekly, n=1379 pts

• Health related patient reported

outcomes comparable between

placebo and Epoetin- alfa at EOT

and 6 mo post CT

• No difference in FFTF and OS

• No difference in number of

deaths, progressions, relapses,

and VTE

• RBC transfusions reduced

from 4 to 2 (p< 0.001). No

transfusions in 27.4% placebo vs

36.7% ESA (p< 0.001).

Andreas Engert et al. JCO 2010;28:2239-2245

Hodgkin Lymphoma :GHSG HD15EPO Trial

Darbepoetin‐alfa and iv iron after autologous HCT

Beguin et al. American Journal of Hematology 2013 Volume 88, Issue 12, pages 990-996

Hb ≥ 2 g/dL Hb ≥12 g/dL

group 1 no DA

group 2 DA,

group 3 DA + iron

http://onlinelibrary.wiley.com/doi/10.1002/ajh.v88.12/issuetoc

DA 300 µg 2 w day

28+

DA + iv iron 200mg

D 28,42,56

Time to Hb + 2 g/dL

% D126 post-HCT) 88 1000.0231

Median D after DA 28 25

Time to Hb = 12 g/dL

% D126 post-HCT) 87 1000.0059

Median D after DA 33 23

RBC transfusions

N patients (y/n) 5/45 0/46 0.0276

N units/patient 0.3 ± 1.4 0 NS

DA and intravenous iron after Autologous SCT



Darbepoetin‐alfa and iv iron after autologous HCT


A-C group 1 no DA, group 2 DA, group 3 DA + iron

Hb levels sTfR levelsReticulocytes


Bloodless stem cell transplant schema

Brown et al. BMT 2009;22:391-2

Prospective randomised trial n= 131

Cumulative incidence of complete response (Hb ≥13 g/dL) from rhEPO

Aurélie Jaspers et al. Blood 2014;124:33-41

Myeloablative

NMHCT D+28

NMHCT D+0

rhEPO after allogeneic HCT



Myeloablative NMHCT D+28 NMHCT D+0

Hb levels higher and transfusion requirements less (p<0.001) in ESA group

No advantage to starting ESA on D0

Allogeneic SCT: Proportions of transfused patients after starting rhEPO.



Myeloablative NMHCT D+28 NMHCT D+0

Take-home Messages

• ESAs are not recommended for anemia due to cancer (Exception =

MDS)

• ESA are recommended for treatment of chemotherapy-associated

anemia

• ESA reduce transfusion requirements , improve QOL, increase VTE

• ESA response must be monitored

• Meta-analysis indicate an overall neutral risk of death for patients

receiving ESA’s

• Intravenous iron replacement is more effective

• VTE’s: role of iron restricted erythropoiesis

The Role of ESA’s in Lymphoproliferative -...

Documents

Transcript of The Role of ESA’s in Lymphoproliferative -...