Transfusion Support in Hematology-Oncology

PatientsDarrell J. Triulzi, M.D.

Professor of Pathology

University of Pittsburgh

Medical Director

The Institute for Transfusion Medicine

Pittsburgh, PA

Transfusion Support in Hematology/Oncology Patients

• Platelet therapy

• Leukoreduction

• Transfusion transmitted CMV

• Irradiated Blood Components: Prevention of Transfusion associated Graft vs Host disease

Blood Products

Whole Blood

Packed RBCs

Platelet-rich Plasma

Platelets

Plasma

Cryoprecipitate

Plasma Derivatives

Albumin

IVIg

Cryoppt-reduced Plasma

Whole Blood Platelets

• 60 ml each (approx.)• >5.5 x 1010 platelets/bag• Storage: 5 days at room temp,

constant agitation• Dose: 1 unit/10 kg up to 40 kg

Adults (>40 kg) - Pool of 4 (= 1 unit of apheresis plts)

plt ct 20 – 35K

Whole blood platelet concentrate

Apheresis Platelet Donation

-1.5 -2.0 hr donation

-Returns red cells and plasma

- Collects 1-3 full adult doses of plts

Apheresis Platelets

• 200-400 ml• >3.0 x 1011 plts/bag

(equiv to 5-6 WBPCs)• Storage: 5 days @ room

temp, constant agitation• Dose: 1 apheresis plt

product per transfusion– plt ct 20 – 40K

Apheresis Platelets

• 200-400 ml• >3.0 x 1011 plts/bag

(equiv to 5 WBPCs)• Storage: 5 days @ room

temp, constant agitation• Dose: 1 apheresis plt

product per transfusion

Single Donor Platelets

Clinical Indications for Platelets

• Significant bleeding in a patient with thrombocytopenia

• Planned invasive procedure in a patient with thrombocytopenia

• Risk of spontaneous bleeding (eg CNS, lung) due to severe thrombocytopenia

• Bleeding or invasive procedure and platelet dysfunction

Transfusion for Bleeding Achieving hemostasis in bleeding thrombocytopenic patients

Cessation of overt bleeding in 51/57 episodes when plt increment exceeded 40K

Cessation of overt bleeding in 17/18 pts when plt increment exceeded 30-40K

Investigator ObservationFreireich, Ann Int Med 1963;59:277

Djerassi, NEJM 1963;268:221Recommendation: Transfuse to > 50K

Transfusion for Surgery

Invasive Procedures

No increase in bleeding complications w/ plt ct 50-100K vs. > 100K

No excess surgical bleeding when plt ct > 50K

Toy, 1990, 1991

Minor procedures: thoracentesis, line placement, etc.

Bishop, Am J Hematol 1987;26:147 - Major intra-abdominal/ intra-thoracic surgeriesRecommendation: Transfuse if < 50K

Investigator Observation

Prophylactic Transfusion

Stool blood loss in 28 aplastic, thrombocytopenic patients

Ann. Review of Med, Vol. 31, 1980

Bleeding risk vs. plt ct The Lancet, Vol. 338, 1991

Platelet Count/μL x 103

255 10 15 200

50

100

25

75

Sto

ol B

lood

Loss

(ml /

day)

0 00 - 5

25

150

75

300

Ble

ed

ing

Ep

isod

es/1

00

0

days

6-10

11-15 16-20 >20

n=

28

0

n=

68

7

n=

80

5

n=

64

2

n=

35

88

Minor BleedingMajor Bleeding

Risk Category by Plt Ct/μL x 103

Prophylactic TransfusionThreshold for Prophylactic Plt

Transfusion in Adult AML• 225 new AML pts (not m3)

• Random, prospective

• A: (135) Tx @ < 10K

• B: (120) Tx @ < 20K

• 21.5% fewer plt Txs in 10K grp

• No signif difference in RBC Txs

• Major bleeding: • 21.5% (10K) vs 20% (20K),p=0.41)

Risk similar 10 vs. 20K threshold Rebulla et al. NEJM, 337:26:1872-5, 1997.

Safety & Cost-Effectiveness of 10K vs. 20K Platelet Trigger

• 105 new AML pts (not M3)

• Prospective, 17 centers

• A: (110) 10K vs. B: (106) 20K

• Less plt Txs (~60%) in 10K grp

• No signif difference in RBC Txs

• Bleeding (WHO grade 2-4):

18% vs. 17% (p=0.8)

One-third lower cost w/ 10K vs. 20K trigger w/ no associated increase in bleeding risk

Wandt H et al. Blood, 91:10:3601-6, 1998.

0

5

10

15

20

25

30

>10091-95

81-8571-75

61-6551-55

41-4531-35

21-2511-151-5

PLATELET COUNT (x 103/L)

DA

YS W

ITH

≥ G

RA

DE

2 B

LEED

ING

(%

)

*Data from 1,272 patients with morning platelet counts on 24,309 days.Data reported as percentage with 95% confidence intervals.

PERCENT OF DAYS WITH ≥ GRADE 2 BLEEDING PERCENT OF DAYS WITH ≥ GRADE 2 BLEEDING VERSUSVERSUS EACH DAY’S MORNING PLATELET COUNT* EACH DAY’S MORNING PLATELET COUNT*

Prophylaxis vs No Prophylaxis

• 600 patients randomized to Prophylaxis at 10k/ul vs no prophylaxis

• Both groups given plt tx for bleeding or procedures

• >15 yo with hematologic malignancy or stem cell transplant

• Assessed daily for bleeding• Primary endpoint rate of WHO ≥grade 2 bleeding

Stanworth et al NEJM 2013;368:1771-80

Baseline Characteristics

Stanworth et al NEJM 2013;368:1771-80

Prophylaxis vs No Prophylaxis

Stanworth et al NEJM 2013;368:1771-80No deaths from bleeding

Indications for Platelet Transfusions in Heme-Onc Patients

• To control or prevent bleeding due to deficiencies of platelet number or function

• Plt ct <10K/μL – prophylaxis, stable pt• Plt ct <20K/μL – prophylaxis in patient

with clinical factors such as sepsis, DIC, high fevers, splenomegaly

• Plt ct <50K/μL – bleeding or undergoing invasive procedure

Platelet Transfusions for Platelet Dysfunction

Cause Mechanism Test Role for Plt Tx?

Aspirin Irreversible inhibitor COX

Abn PFA eg closure time

Yes

NSAIDS Reversible inhibitor COX

Abn PFA eg closure time

Usually not needed

Clopidogrel

P2Y ADP receptor inhibitor

Verify Now (Accumetrix), aggregometry

Yes

CP Bypass

Plt activation on membrane

Abn PFA eg closure time

YES

Uremia Accumulation of metabolic inhibEg guanidino succinic acid

Abn PFA eg closure time

No, Use Dialysisand DDAVP

Platelet Refractoriness

Hours

0 12 24

Pla

tele

t C

ou

nt

40K

20K

10K

63

Usual Response

Disease-related platelet consumption:

Bleeding, Sepsis, DIC, Splenomegaly, VOD, Amphotericin B, etc.

Antibody Mediated:Plt crossmatching, HLA-matched

30K

Indications for Apheresis Platelets

• To control or prevent bleeding in patients refractory to WBPCs (HLA-matched or cross-match compatible platelets)

• To reduce donor exposures in patients receiving a limited number of transfusions

• Otherwise, same as for WBPCs

Contraindications to Platelet Transfusion

• Plt ct >100K/μL w/o platelet dysfunction• ITP or TTP unless bleeding is life-threatening

• Prophylactic use with massive blood transfusion

• Prophylactic use following cardiac bypass

Recent advances in Platelet Transfusion Practice

Does the dose of platelets transfused affect hemostasis in thrombocytopenic patients?

How important are the characteristics of the platelet component such as the source, ABO matching, or storage duration in prevention of bleeding?

Platelet Recovery and Survival

Hours Post transfusion

0 12 24

Pla

tele

t C

ou

nt

50K

25K

10K

63

Usual Response

Recovery CCI >7500

Survival CCI>4500

“DETERMINATION OF THE

OPTIMAL PROPHYLACTIC PLATELET DOSE

STRATEGY TO PREVENT BLEEDING IN

THROMBOCYTOPENIC PATIENTS”

(PLADO Trial)

Study was conducted at 26 participating hospitalswithin the Transfusion Medicine/Hemostasis Clinical Trials Network

supported by the National Heart, Lung and Blood Institute of the National Institutes of Health

Slichter SJ, Kaufman RM, Assman SF, McCullough J, Triulzi DJ, et al. Dose of prophylactic platelet transfusions and

prevention of hemorrhage. New Eng J Med 2010;362:600-13.

*Medium dose corresponds most closely to the current standard transfusion dose of 6 pooled platelet concentrates or 1 apheresis platelet collection.**An acceptable dose was within 25% either above or below the target dose. The transfusion service was given each patient’s study dose but not the patient’s randomization arm.

STUDY DESIGNSTUDY DESIGNThree-Arm

ProspectiveRandomized Trial) Platelets / m2(BSA)**

Medium Dose (MD)* 2.2 x 1011

Lower Dose (LD) 1.1 x 1011 (½ MD)

Higher Dose (HD) 4.4 x 1011 (2x MD)

Platelet Dosing StudyPlatelet Dosing StudyLow Med High Total

Number of patients enrolled 453 449 449 1351

Number of patients with 1 platelet transfusion* 417 423 432 1272

Primary Endpoint: At least one episode of Grade 2 bleeding 71% 69% 70% 70% (% of patients)

Secondary Endpoints: Highest grade of bleeding on study

(% of patients): None or Grade 1 30% 32% 30% 31% Grade 2 58% 59% 60% 59% Grade 3 9% 7% 8% 8% Grade 4 3% 2% 2% 2%

Hemorrhagic mortality (# of patients) 0 0 1 1

*All data reported will be based on patients who received 1 platelet transfusion.

There were no significant differences among the arms for any of these study endpoints. NEJM 2010;362:600-13.

How important are the characteristics of the platelet component such as the source, ABO

matching, or storage duration in prevention of bleeding?

p=0.72

Time Since First Platelet Transfusion (Days)

Pro

babi

lity

of R

emai

ning

Eve

nt F

ree

0 5 10 15 20 25 30 35

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

ApheresisWBP

No. Patients at Risk

Apheresis

WBP

552 338 168 68 32 16 4

220 119 56 30 15 5

PLADO: Platelet Source as a predictor of ≥ Grade 2 bleeding

Time Since First Platelet Transfusion (Days)

Pro

ba

bili

ty o

f R

em

ain

ing E

vent F

ree

0 5 10 15 20 25 30 35

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

ABO IdenticalMinor MismatchMajor Mismatch

No. Patients at RiskABO Identical

Minor MismatchMajor Mismatch

467 215 78 31 10 3 175 30 8 2 1198 72 27 5

p=0.28

PLADO: ABO matching as a predictor of time to ≥ Grade 2

bleeding

Time Since First Platelet Transfusion (Days)

Pro

ba

bili

ty o

f R

em

ain

ing

Eve

nt

Fre

e

0 5 10 15 20 25 30

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0-2 Days3 Days4 Days5 Days

No. Patients at Risk0-2 Days

3 Days4 Days5 Days

48 13 5158 47 16 1223 69 13 1221 71 23 4 1

PLADO: Duration of platelet storage as a predictor of time to ≥ Grade 2

bleeding

p=0.87

PLADO: Analysis of Platelet Characteristics

Summary• Although the source of platelets, ABO

matching, and duration of storage have a measureable effect on platelet increments, there is no discernable effect of these platelet characteristics on a bleeding outcome when platelet transfusions are used prophylactically in hematology and oncology patients

Transfusion Support in Hematology/Oncology Patients

• Platelet therapy

• Leukoreduction

• Transfusion transmitted CMV

• Irradiated Blood Components: Prevention of Transfusion associated Graft vs Host disease

Leukoreduction: Definition

• AABB Standards

5.7.4.1 “ Leukocyte reduced blood and components shall be prepared by a method known to reduced the leukocyte number to <5x106 for apheresis platelets and Red Blood Cells…”

Leukoreduction by Filtration

Filter Generation Filter composition

Mechanism Filter efficiency

Log10

First 170-240u nylon mesh

barrier -

Second 40u polyester barrier 1

Third Nonwoven synthetic fibers

Barrier and adsorption

3-6

>99.9%

Accepted Indications for Leukoreduction

• Reduce the risk of fever chill non-hemolytic reactions

• Prevent or delay alloimmunization to HLA antigens

• Reduce the risk of CMV transmission

Febrile, Non-Hemolytic Transfusion reactions

Symptoms & Signs• Fever (temp rise at

least 1° C or 1.8° F)• Chills• Dyspnea• Tachycardia• Flushing• Hypertension“Fever-Chill” Reaction

Febrile, Non-Hemolytic TR

Etiology:• Recipient Ab’s to

transfused WBCs• Cytokines in

transfused product

Leukoreduction Reduces the Rate of FNHTR

Author Non-LR

RBC

LR

RBC

Non-LR

Plts

LR

Plts

Yazer*

2004

0.33% 0.19%

p<.001

0.45% 0.11%

p<.001

Paglino*

2004

0.34% 0.18%

p<.0001

2.18% 0.15%

p<.0001

King*

2004

0.37% 0.19%

p=.0008

NA NA

*Transfusion Jan 2004 Vol 44.

Accepted Indications for Leukoreduction

• Reduce the risk of fever chill non-hemolytic reactions

• Prevent or delay alloimmunization to HLA antigens

• Reduce the risk of CMV transmission

Trial to Reduce Alloimmunization to Platelets (TRAP)

05

10

15

2025

30

35

40

4550

Control UVB -PC F-AP F-PC

Perc

en

t A

lloim

mun

ized

F-AP = filtered apheresisF-PC = filtered pools

UVB-PC = Ultraviolet B irrad

New Eng J Med 1997; 337:1861-9.

530 patients with AML randomized to 4 platelet therapies

p<.001 for all 3 study arms

Trial to Reduce Alloimmunization to Platelets (TRAP): Refractoriness

02

4

6

810

12

14

16

1820

Control UVB -PC F-AP F-PC

Perc

ent

refr

act

ory

F-AP = filtered apheresisF-PC = filtered pools

UVB-PC = UVB irrad

New Eng J Med 1997; 337:1861-9.

530 patients with AML randomized to 4 platelet therapies

p≤.03 for all 3 study arms

Accepted Indications for Leukoreduction

• Reduce the risk of fever chill non-hemolytic reactions

• Prevent or delay alloimmunization to HLA antigens

• Reduce the risk of CMV transmission

Transfusion Transmitted Cytomegalovirus

CMV in Blood Donors

• 30-80% of blood donors are CMV seropositive . Prevalence increases with age.

• CMV is transmitted in a latent non-infectious state in the donor leukocytes.

• CMV is transmitted only by cellular blood components eg. red cells, platelets

CMV in Auto or Allo BMT

Concept of CMV “Safe” Blood Components

• Leukoreduction can substitute for CMV seronegative components– CMV exclusively WBC associated– >3 log (99.9%) leukoreduction removes virus and greatly

reduces infectivity

• Conserves seronegative units for patients at highest risk

• More readily available

CMV Safe Auto BMT

Randomized Trial of CMV Safe vs Seronegative Blood in Allogeneic Stem Cell

TransplantationSeroneg

N=252

CMV safe

N=250 p valueCMV infection

Day 21-100

Day 0-100

2

4

3

6

1.0

.5

CMV disease

Day 21-100

Day 0-100

0

0

3

6

.25

.03

Mean RBC units 18 18 NS

Mean plt units 83 85 NS

Bowden R, et al Blood 1995;86:3598

Indications for CMV Seronegative Components

• Seronegative recipient of a seronegative allogeneic stem cell transplant

• Seronegative allogeneic stem cell transplant candidate

Indications for CMV “SAFE” cellular components

• Autologous stem cell transplant recipient regardless of CMV serostatus

• All hem-onc patients who are not allogeneic stem cell transplant candidates

• Any heme/onc or stem cell transplant patients known to be CMV seropositive

Transfusion Associated Graft versus Host Disease

(TAGVHD)

TAGVHD

• Results from engraftment of foreign T cells from cellular blood components

• Clinically similar to GVHD from stem cell transplantation except pancytopenia is a prominent feature

• Usually presents with high fever and rash within 3-30 days of transfusion

• Unresponsive to therapy: mortality exceeds 90%!

Organ Involvement in TAGVHD

Site Stem cell transplantation

Transfusion

Skin ++ ++++

Liver ++ ++++

GI tract ++ ++++

pancytopenia - ++++

Prevention of TAGVHD

• Gamma irradiation of cellular blood components (Cesium, Cobalt, X-ray)

• Minimum 2500 rads acheives 5-6 log reduction in T cell mitogen response

• Does not cause clinically significant damage to the blood component

• RBC experience some K+ leak, shelf life shortened to 28 days

Cell Irradiator

Irradiation Confirmation Sticker:“NOT” should not be visible

Indications for Irradiated Cellular Blood Components

• Stem cell transplant recipients (auto or allo)• Patients with congenital immunodeficiency syndromes eg

SCIDS, Wiscott-Aldrich, DiGeorge• Patients with Hodgkins disease• Patients receiving fludarabine• Directed blood from blood relatives• HLA matched platelets• OPTIONAL for leukemia/lymphoma, usually done• Not recommended for patients with solid organ

malignancy

Irradiated

CMV Negative

Leukoreduced

Zou S et al Transfusion 2010;50:1495.

Virus

1996

2001 2013

HIV 1:493,000

1:1,326,000

1:1,470,000

Hepatitis C

1:103,000

1:237,0001:1,150,000

Hepatitis B

1:63,000

1:137,000<1:300,000

HTLV I, II

1:641,000

1:641,000 1:2,437,296

Estimated Risks of Viral Transmissions in US

62C O N F I D E N T I A L