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(9309-TC-CT)

Infusion Practices in Cellular Therapy:

Current Practice and Future Direction 

 

October 8, 2012 10:30 AM - 12:00 PM  

 

Event Faculty List

Event Title: 9309-TC-CT: Infusion Practices in Cellular Therapy: Current Practice and Future Direction

Event Date: Monday, October 8, 2012 Event Time: 10:30 AM to 12:00 PM

Director/Moderator/Speaker Karen Snow, BS, BB(ASCP) Quality Manager, Bone Marrow Transplant Program Massachusetts General Hospital ksnow1@partners.org Disclosures: No

Speaker Michael Linenberger, MD Medical Director, Apheresis & Cellular Therapy Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance linen@u.washington.edu Disclosures: Yes

Speaker Olive Sturtevant, MHP, MT(ASCP)SBB, SLS, CQA(ASQ) Quality Assurance Director Dana Farber Cancer Institute olive_sturtevant@dfci.harvard.edu Disclosures: No

07/11/2012

1

Michael Linenberger, MD FACP

Associate Member, Clinical Research Division, Fred Hutchinson Cancer Research Center

Medical Director, Apheresis and Cellular Therapy, Seattle Cancer Care Alliance

Associate Professor, Hematology Division, University of Washington School of Medicine

and a Really Nice Guy

Olive Sturtevant, MHP, MT(ASCP)SBB, SLS, CQA(ASQ)

Director of Quality Assurance for Cellular Therapy Programs at the Dana Farber Cancer Institute

1

The Care & Handling of Stem Cell Products & Recipients at

the Time of Infusion

Michael Linenberger, MDMedical Director, Apheresis & Cellular Therapy

Cancer Care Alliance/Fred Hutchinson Cancer Research Center/Seattle

AABB Annual Meeting October 8, 2012

Disclosure InformationMichael Linenberger, MD

I have no financial relationships to disclose

Objectives

• Review the composition of blood & marrow HPC products for stem cell transplantation

• Discuss the management of patients undergoing infusion of HPC products

• Case-based presentations & discussion of infusion-related adverse events (AEs)

• Strategies to mitigate infusion-related AEs

2

HPC, Marrow Product

Infuse fresh

± manipulation ± cryopreservation

HPC, Marrow Product • Std volume goal: 10 – 15 mL/kg recipient wt• Std TNC goal: 2 – 4 x 108 TNC/kg recpt wt• Final HPC(M) Product

- Volume: 700 – 1500 mL (adult recipient)

- TNC count: 22 – 32 x 109/L (0.5 – 1% CD34+)

- TNC content: ~ 15 – 40 x 109

- Hematocrit: 20 - 30% - RBC vol: 180 - 380 mL

- Final anticoagulant/Buffer: Heparin 10 units/mL

in 10% Normosol-R or Plasma-Lyte A or ACD-A

HPC, Apheresis ProductMobilization w/ chemoRx &/or G-CSF ± plerixafor

Infuse fresh

Cryopreserve thaw/infuse

http//www.bloodca

3

HPC, Apheresis Product • Blood vol. process: 3x – 6x TBV (12 – 36 L)

• Std CD34+ goal: 2 - 5 x 106 /kg recpt wt/Txpl*

• Final HPC(A) Product** (for 12 L bld vol. process)

- Vol: 120 - 200 mL - Hct: 1 - 3% (2 - 6 mL RBC)

- TNC content**: ~ 15 – 70 x 109 CD34+: 0.2 – 1.5%

- MNCs**: 55 - 75% Granulocytes**: 25 – 55%

- Anticoagulant: ACD-A (6 - 8%) ± Heparin ~1 U/mL

• Cryoproduct: 10% DMSO + plasma or HSA + buffer

• Infusion: Thaw at bedside & infuse ASAP

HPC, Cord Blood Product

In Utero PlacentaHarvest

asherbenjamin.netjci.org

Ex utero or in utero harvest

into CPD(A)

Cryopreserve in5-10% DMSO ± dextran

http//www.taq.com

Thaw/dilute in labin dextran 40 + HSA

RBC-deplete*in HES andconcentrate

SCIENCEphotoLIBRARY*Some products RBC-replete

Infusion of Fresh HPC Products

Clinical Considerations*• Volume load: HPC(M) & peds

• ABO MM: Major w/ RBC > 20 mL;

Minor w/ plasma > 200 mL [titers]

• Hx transfusion Rxn: Pre-meds

• Heparin: aPTT; Hx of HIT(T)**

• ± Filter (institutional guideline)

• Monitoring: 15 min prior; q1hr during; for 2 hr post-infusion

*Sauer-Heilborn et al. Transfusion 2004;44:907

HPC product

**Heparin-induced thrombocytopenia (thrombosis)

4

Infusion of Cryopreserved HPCsClinical Considerations*

• Post-thaw wash / dilute (UCB)

• Central venous access (for DMSO)

• DMSO: Dose 1 gm/kg (10 mL/kg)

– IV hydration: 2 hr pre 5 hr post

– Pre-meds: H1 blocker; antiemetics;hydrocortisone

• Dextran 40 (HES) (UCB)

• ± Filter (institutional guideline)

• Monitor: 15 min pre q15-30 min up to 4-24 hr post; *Emergency Meds*

*Sauer-Heilborn et al. Transfusion 2004;44:907

HPC product

Case 1: 23 yo with Aplastic Anemia• PMH: AA x 4 mo; o/w healthy

• Pre-Txpl: 80 kg; LVEF 69%

• Cond: Cytoxan, ATG, TBI

• URD HPC(M): ABO matched

– 30 hrs old – TNC 24.2 x 109

– 1200 mL infused over 8 hrs

• 4 hr post-infusion: SOB;

O2 sat’n 78% ICU/intubated;

EKG, troponin & BNP nl; PTT 39s

Case 1: Follow-up • Differential diagnosis

– TACO: Echo LVEF 65%; CVP 10

– Diffuse alveolar hemorrhage: Bronch / BAL (–)

– Sepsis/ARDS: Blood & BAL cultures (–)

– Product contamination: Gm stain (–); culture (P)

• Course: Resolved w/supportive care in 36 hr

– TRALI*: Pt sera (+) for non-HLA antibodies

*Urahama et al. Transfusion 2003;43:1553

SCCA HPC(M) AEs: 25% gr I-II; fever, N/V, hives, BP (peds)

5

Culture-Positive HPC Products• Incidence: 0.2 – 26% (Recent: HPC(M) & HPC(A) ~1 – 7%)

• Higher rates: HPC(M) > HPC(A); manipulated products; LVL HPC(A)6 & pre-cryopreservation (vs post-thaw)

• Organisms: Coag (–) Staph > S. aureus > Bacillus, Corynebacterium, Propionibacterium

• Recipient Outcomes: No increase in infusion-related AEs; very rare 2o bacteremia or other clinical sequelae; no effect on engraftment or txpl course

• ± Prophylaxis for culture (+) cryo HPC product

1Kamble et al. Transfusion 2005;45:874 2Padley et al. Transfusion 2007;47:636 3Vanneaux et al. Cytotherapy 2007;9:508 4Klein et al. BBMT 2006;12:1142 5Patah et al. BMT 2007;40:365 6Donmez et al. Transfusion 2012;52:777

Case 2: 59 yo Relapsed B-Cell NHL

• PMH: Htn; CAD/pacemaker; DM

• Pre-Txpl: 87 kg; lung nodules

• Cond: Bu/VP-16/Ara-C/Melph

• Auto HPC(A): 2-days (22 bags)

• Day 1: 580 mL in 10 bags N/VBP; 2 hrs post-infusion CP, troponin NL, EKG: OK ( QTc !)

• Day 2: 10th bag (500mL) N/V; SOB & O2 satn severe CP

EKG: Anterior ischemia

Rapid deterioration to V-fib

Code Blue: Not resuscitated

Butler J M J Accid Emerg Med 2000;17:426

DMSO-Related Adverse Events

• Highly polar, permeable cryoprotectant

• Hyperosmolar (1800 mOsm) venotoxic

• Histamine-mediated AEs: 15 - 50%– Nausea/vomiting – Throat tickling – BP

– Cough – Flushing – Hiccup – Dyspnea

• Mitigation strategies– Antihistamines – Antiemetics

– Corticosteroids

6

DMSO-Related Histamine AEs

Mitigation strategies– Aromatherapy

Ozdemir et al. BBMT 2008;14:1425

Potter et al. Cancer Nurs 2011;35:361 http://www.aromatherapy-regulation.org.uk/ICANHASCHEEZBURGER.COM

DMSO-Related Adverse EventsCardiovascular* / myocardial / vasogenic effects

– Tachycardia / bradycardia / heart block

– Hypertension / hypotension; creatinine

– Mild & transient; risk with AL amyloidosis

• Neurologic (usually transient & mild)

– Headache; LOC; amnesia; confusion; delirium

• Rare SAEs (? pathogenic mechanisms ?)

– Anaphylactoid – MI – Acute renal failure

– Encephalopathy, seizure, stroke (paradoxical embolism)

*Fitzhugh et al. Blood 2012;119:5671 – No difference in BP, TRV, creat w/ Cryo PBSC vs non-cryo

Does Removal of DMSO Reduce Infusion Related AE Incidence?

Adapted from: Windrum et al. BMT 2005;36:601

Survey of EBMT Transplant Centers

Per

cen

tag

e In

cid

ence

AE

s

All 5% DMSO 5–10% 10% Washed Not(n=95) (9) (6) (78) washed

*Adapted from: Sanchez-Salinas et al. Transfusion 2012; 8 Mar [Epub]

7

Infusion Related AEs Are Related to Cryoproduct TNC/PMN Content*

*Calmels et al. Transfusion 2007;47:1268

n=10n=56

0

8

Med

. nu

mb

er P

MN

s (x

109 )

1 - 2 3 - 4

Prefreeze PMN content vs AE severity

28

58

n=55 n=10Med

. CD

45 v

iab

ility

(%

)

Post-thaw CD45 viability vs AE severity

0 1 - 2 3 - 4

71

48

58

412

• N = 460 No. infusions = 490 DMSO removed

• Gr 3 - 4 events: LOC; seizure; cardiac arrest

Case 2: 59 yo Relapsed B-Cell NHL• SAE: Myocardial ischemia V-fib arrest death

• Autopsy: Acute coronary thrombosis; severe CAD

• Other recent SCCA cases of infusion related SAEs

– 60 yo, refractory HL: Acute renal failure / dialysis

– 48 yo, plasma cell leukemia: Rapid multi-organ failure with death 30 hrs after infusion

Patient DMSO TNC/kg Gran/kg (%TNC)

Case 2 (NHL) 0.69 gm/kg 3.75 x 109 2 x 109 (54%)

Hodgkin lymphoma 0.78 gm/kg 3.05 x 109 2.3 x 109 (65%)

Plasma cell leukemia 0.95 gm/kg 6.14 x 109 4.6 x 109 (76%)

Patients InfusedQ1 Q4Q3Q2

Quartile Analyses of Cryo HPC(A) Infusions (n=411): TNC/kg vs AEs

Gr 3: Severe, requires interventionGr 4: Life-threateningGr 5: Fatal 1.63 x 109/kg

Quartile TNC/kg

Q2Q1 Q3 Q4

8

SCCA Cryoproduct Infusion Policy Change to Limit TNC Dose

• New policy: Deliver 1.63 x 109 TNC/kg/day

• Implementation date: 12/4/2007

• 2010: Retrospective comparison from 18 mos pre-policy change (n=327) to 21 mos post-change (n=456)

– Infusion-related AEs frequency and severity

– Days of infusion

– Days to neutrophil engraftment

Cryo HPC(A) Infusion Days

(p<0.0001)

Pre-policy (n=327)

Post-policy (n=456)

Number of Days

% P

atie

nts

(M

ean

)

0102030405060708090

100

1 2 >2

7.9%0.6%

16.7%

5.8%

75.4%

93.6%

Khera et al. BBMT 2012;18:220

3 days: 24 pt4 days: 12 pt5 days: 1 pt

Product Content & Clinical Outcomes: Pre- vs Post-Policy Change

Parameter Pre-Policy (n=327)

Post-Policy (n=456) p value

Median CD34 x 106/kg/HCT (range)

6.38 (0.22 - 59.25)

6.33 (0.81 - 87.04)

NS

Median TNC x 109/kg/HCT (range)

0.87 (0.09 - 8.64)

0.87 (0.05 - 7.26)

NS

Median # infusion days

(range)

All HCTs 1 (1 - 4) 1 (1 - 5) NS

> 1.63 x 109 TNC/kg 1 (1 - 4) [n=82] 2 (1 - 5) [n=112] <0.0001

Median # days to neutrophil engraftment 14 14 NS

Infusions with grade 3 - 5 SAEs (%)

13(3.98%)

3(0.66%)

0.001

Khera et al. BBMT 2012;18:220

9

Product Content & Clinical Outcomes: Pre- vs Post-Policy Change

Parameter Pre-Policy (n=327)

Post-Policy (n=456) p value

Median CD34 x 106/kg/HCT (range)

6.38 (0.22 - 59.25)

6.33 (0.81 - 87.04)

NS

Median TNC x 109/kg/HCT (range)

0.87 (0.09 - 8.64)

0.87 (0.05 - 7.26)

NS

Median # infusion days

(range)

All HCTs 1 (1 - 4) 1 (1 - 5) NS

> 1.63 x 109 TNC/kg 1 (1 - 4) [n=82] 2 (1 - 5) [n=112] <0.0001

Median # days to neutrophil engraftment 14 14 NS

Infusions with grade 3 - 5 SAEs (%)

13(3.98%)

3(0.66%)

0.001

Khera et al. BBMT 2012;18:220

Policy Change at SCCA• HPC(A) cryoproducts with high numbers of TNC

and granulocytes are associated with more frequent SAEs, including life-threatening events

• Limiting the dose of TNC/kg/day resulted in more multi-day infusions but without affecting kinetics of post transplant neutrophil engraftment

• Avoiding high daily TNC/kg dose infusions led to a significant reduction in grade 3 – 5 SAEs

Case 3: 15 yo Refractory NHL

• PMH: NHL; o/w healthy

• Pre-Txpl: 50 kg; febrile txf rxns

• Cond: Fludara / Cytoxan / TBI

• HPC(CB): 2 units; 5/6 Ag matches

• Bag #1: RBC depleted; thaw/dilute; 280 of 400 mL infused acute BP; SOB/wheezing; facial edema; hives

Actions: Epinephrine IM; IV fluids, IV hydrocortisone & diphenhydramine; bronchodilators

Anaphylaxis

10

Case 3: Anaphylaxis w/ HPC(CB)

• Priority #1: Patient safety (Resp & CV status)

• Priority #2: BMT considerations (engraftment)– TNC received from bag #1? 2 x 107/kg

– Bag #2: RBC replete thaw/wash; 3 x 107 TNC/kg

• What in bag #1 caused anaphylaxis?– Plasma Ag – DMSO – Dextran 40 – Cell debris

• Can we “wash” bag #2 & infuse safely? – TNC recovery? – Remove offending agent?

Infusion AEs w/ HPC(CB) • Thaw & infuse (1 unit)

17% mild AEs1: BP, dyspnea

9% non-CV AEs2; – But 30 – 64% or BP, bradycardia

• Thaw & wash (mild & transient) 10% with 1 unit1: BP, dyspnea, fever

40% with 1 of 2 units3: BP, N/V, tingling

• Thaw & dilute (mild & transient) 10% with 1 unit 1: BP, bradycardia, N/V, dyspnea

65% with 1 of 2 units4: BP >> N/V, bradycardia

1Regan et al. Transfusion 2010;50:2670 2Konuma et al. BMT 2008;41:861 3Barker et al. Blood 2005;105:1343 4Barker et al. BBMT 2009;15:1596

SAEs w/ HPC(CB) Infusions • Concern with RBC replete units (> 20 mL RBC)

– Hemolysate*: Free Hgb, stroma, RBC membranes

– Bradycardia & hemoglobinuria (similar to auto BM1)

• “Stunned heart” syndrome2-5 [RBC replete >> depleted]

– Acute cardiopulmonary decompensation [CHF]

– Chest pain, BP, O2, N/V; troponin, LVEF; creatinine

– Usually reversible w/supportive care

• Anaphylactic(toid) reactions2,5 [RBC-depleted units]

• ? Mechanism ?: DMSO, hemolysate, Dextran 40 (anaphylaxis)

– Dextran sensitivity: ? IV test dose ? Dextran 1 prophylaxis6

1BMT 1999;23:533 2Acta Haematol 2009;122:1 3Miller. BB-IND #7555 Safety Report. NMDP:July 2009 4Am J Hematol 2010;85:722 5Transfusion 2012;52:207 6J Vasc Surg 2006;43:1004 *Fitzhugh et al. Blood 2012;119:5671

11

Case 3: Anaphylaxis w/ HPC(CB)• Patient signs & symptoms resolved w/in 4 hr• What did we do with bag #2 ???

– Already thawed/washed: ~ 60 mL + dextran 40

– Manual “wash” x2 w/ 250 mL Normosol-R + HSA

– TNC recovery post-wash: 1.8 x 107/kg

– TNC viability post-wash: 75%

• Pre-meds: w/ diphenhydramine; HC; H2-blocker

• Infusion: ‘Test dose’ slow infusion in ICU

• Success! No reaction/sequelae; engraftment d22

Summary: HPC Infusion AEs

• Product cellular &/or solute constituents can trigger acute or delayed AE signs/symptoms

• Cryopreserved HPCs have unique risks/AEs

• Experienced personnel must plan, supervise & monitor HPC infusions & treat AEs

• Prophylactic & mitigation strategies must be utilized on a routine & patient-specific basis

• Further measures sought to optimize safety

1

Welcome to New England

11/7/2012 1

Adverse Event Reporting in Cellular Therapy

Where we are and where should we go from here?

11/7/2012 2

Karen SnowQuality Assurance OfficerBone Marrow Transplant ProgramMassachusetts General Hospital

Objectives

Review data on adverse reactions involving DMSO

Examine current practices in reporting of adverse reactions to HPC product infusion

Investigate the use of tools to improve reporting of these events

11/7/2012 3

2

Special Objective:

Invite and encourage input from professionals in the field to work on improving recognition, communication, and reporting of adverse reactions in the field of cellular therapy

11/7/2012 4

DMSO: Frequent Cause of Infusion Reactions

Mild reactions include: Nausea, vomiting

Flushing, hypotension

Restless leg

Moderate to severe reactions may involve multiple organ systems

11/7/2012 5

DMSO: Reaction Related to Dose

Reactions to DMSO related to Dose

DMSO doses above 1g/kg wt have been associated with hemolysis as well as cardiac, renal, liver and other organ system damage

11/7/2012 6

3

Standard Prevention

Premedication prior to infusion of cryopreserved products

Antihistamines

Corticosteroids

Premedication has its own side effects

11/7/2012 7

Prevention of Infusion Reactions to DMSO

One study attempted infusion of washed products without premedication

Study halted early after 1 of 5 patients experienced severe toxicity attributed to the lack of premedication

Rowley et al. Cytotherapy (1999) Vol. 1, No. 6, 439–446

11/7/2012 8

Prevention of Infusion Reactions

Removal of DMSO at thaw

Limit infusion volume

Alternate freezing solutions

Cryopreservation using lower concentration of DMSO

TRANSFUSION 2010;50:2158-2166 11/7/2012 9

4

Concentration of DMSO in Cryopreservation

Use of 10% DMSO is widely accepted

Several studies found lower concentrations of DMSO may be equivalent to 10% DMSO in maintaining viability/functionality of cells Hayakawa et al. Transfusion 2010;50:2158-2166

Liseth et al. Transfusion 2009;49:1709-1719

Abrahamsen et al. Transfusion 2004; 44:785-789

Sauer-Heilborn et al. Transfusion 2004; 44:907-916

11/7/2012 10

11/7/2012 11

One Center Experience

Small number of infusion reactions reported

Why?

Utilization of 5% DMSO in freezing solution may result in low numbers of infusion reactions

Under-reporting of adverse reactions

11/7/2012 12

5

Autologous and Allogeneic Transplants 2000 - 2011

11/7/2012 13

Reactions Reported by Product Type2008 - 2012

Total Auto Transplants and Adverse Reactions Reported

11/7/2012 15

0102030405060708090

100

2008 2009 2010 2011 2012

Allogeneic

Cord Blood

Autologous

6

Some of the Variables

Is it the same in other transplant centers? Very mild reactions may go unnoticed

Expected reactions may not be reported

Reporting very subjective

Events may occur after the designated observation period following infusion

11/7/2012 16

Adverse Event Reporting at Other Transplant Centers

2010 AABB Practice Snapshot

Developed by the Product Collection & Clinical Practices Subcommittee

“Recognition and Monitoring of HPC Infusion Reactions”

45 Transplant Centers completed the snapshot

11/7/2012 17

Snapshot Questions:

Basis questions to determine: Level of staff involved in product infusion

Types of forms used to collect/report reactions

Extent of infusion reaction investigation

Who determines the nature and classification of reaction

http://www.aabb.org/resources/bct/ct/Pages/snapshots.aspx

18

7

Snapshot Results:

Methods most often employed to prevent infusion reactions Limit product volume (54%)

Wash all products at time of thaw (7%)

Adjust infusion rate, dose, product dilution ….and other (21%)

11/7/2012 19

Snapshot Results:

How long the patient is monitored following product infusion

Unknown ( 9%)

0 – 2 hours (43%)

0 – 12 hours (14%)

0 – 24 hours (34%)

20

So-Cell Network CommentsInfusion Reactions (Table 5)

Standard Practices among participants: Utilization of Infusion/AE form

Laboratory staff usually involved in product infusion

SOP exists, but does not always specify how long to monitor following infusion

11/7/2012 21

8

So-Cell Network CommentsInfusion Reactions (Table 5)

Different practices: How long patient is monitored for reactions

following product infusion Anywhere from 30 minutes to 24 hours

May depend on product type

Types of reactions reported Scratchy throat, cough not always reported

Extent of reaction workup differs widely

11/7/2012 22

What Should Our Goals Be for Improvement?

Capture all relevant infusion reactions

Accurately grade severity

Determine causality as it relates to product infusion

Develop consistent reporting methods that allow measurement and comparison of data across multiple transplant centers

23

Data Capture not Consistent

Varies with staff performing infusion and if:

Patient is on protocol

Mild adverse reactions may not be caught because they may be inconsequential

Mild adverse reactions when noticed may be alleviated by slowing or pausing the infusion, giving candy, or a glass of water, providing blanket if chills etc and not reported

Candice del Rio, RN Research Nurse MGH

11/7/2012 24

9

Tools to Improve Reporting of Adverse Reactions

Internal tools

NMDP/CIBMTR forms

Future direction: Where should we go from here?

Biovigilance Network

www.aabb.org/biovigilance

25

Internal Tools

Cell therapy infusion form or adverse event form

Data entry electronic/paper medical records

Communication is Key to facilitating information Accurate

Timely

Communicate to proper staff

11/7/2012 26

Infusion/Adverse Event FormInformation Captured:

Adverse Reaction to Infusion? Yes/No Signs and Symptoms ☐ Check for each symptom

Was infusion stopped/restarted?

Medications given

Detail of actions taken (free text)

11/7/2012 27

10

Beyond the Infusion/Adverse Reaction Form:

What other information is necessary Causality

Severity Grading

CTCAE Common Terminology Criteria for Adverse Events

Utilized by clinicians for patients on clinical trials (NCI)

Definition and grading of Adverse Events

11/7/2012 28

CTCAE Grading and Reporting as an Internal Tool

Protocol: Toxicity

_________Grade 1

Patient:Grade 2

_________Grade 3

Date: ___Grade 4 Grade 5 Related to

Study?

Low ANC <LLN - 1.5 x10e9/L

<1.5 - 1.0 x10e9/L

<1.0 - 0.5 x10e9/L

<0.5 x10e9/L

____ yes/pos/no

Fever w/o low ANC

100.4 -102.2°F

102.3 -104.0°F

>104.0°F for ≤24hr

>104.0°F for >24hr

Death yes/pos/no

FEBRILE NEUTROPENIA ANC<1, T>101.3

_______ _______ Present Life-Threatening

Death yes/pos/no

Hypotension Asymptomatic; no intervention

Non-urgent medical intervention indicated

Hospitalization indicated

Life-threatening

Death yes/pos/no

11/7/2012 29

NMDP/CIBMTR forms

NMDP 2006 electronic form specific to CT product infusion

Not required for all transplants Donor/recipient information

Product characteristics

Product manipulation

Possible contamination

Adverse reactions

11/7/2012 30

11

NMDP/CIBMTR forms

NMDP form 3001 Adverse Event

Specific to AE involving CT product infusion

Requested for Matched Unrelated Donor CT products facilitated by NMDP

CTCAE Grade (most severe):

Causality

11/7/2012 31

NMDP/CIBMTR forms

CTCAE Grade (most severe):

Determined by Clinical Staff Grade 1 = Mild, no treatment necessary

Grade 2 = Mild resolved with treatment

Grade 3 = Hospitalization indicated

Grade 4 = Life threatening

Grade 5 = Death

11/7/2012 32

NMDP/CIBMTR forms

Causality: Determined by Clinical Staff

“What is the relationship between the adverse event and the product?” Unrelated

Unlikely

Possibly

Probably

Definitely

11/7/2012 33

12

Future DirectionBiovigilance Network

Bio (Biology)

Living organisms (patients & donors)

Vigilance

Watchfulness

Caution

Observation

Awareness

11/7/2012 34

Future DirectionBiovigilance Network

Transfusion recipient

Blood donor

Tissues & organs

Cellular therapy

11/7/2012 35

Proposed Goals for Cellular Therapy as part of Biovigilance

Network

Develop recommendations for good clinical practice for CT infusion

Investigation of reactions to CT product infusion

Develop guidance for standardization of infusion reaction reporting

11/7/2012 36

13

Proposed Goals for Cellular Therapy

Infusion reaction reporting to include: Centralized reporting system

Uniform terminology

Uniform severity grading

biovigilance@aabb.org

11/7/2012 37

Thank you

Practice Snapshot Participants

So-Cell Network Participants & AABB

Barbara Whitaker (AABB)

Lisa Phillips Johnson (NMDP)

Co-workers and colleagues at MGH

Candice Del Rio, RN

Thomas Spitzer, MD

11/7/2012 38

What it looks like when it’s NOT RAINING!

11/7/2012 39

1

The Care & Handling of Stem Cell Products & Recipients at

the Time of Infusion

Michael Linenberger, MDMedical Director, Apheresis & Cellular Therapy

Cancer Care Alliance/Fred Hutchinson Cancer Research Center/Seattle

AABB Annual Meeting October 8, 2012

Disclosure InformationMichael Linenberger, MD

I have no financial relationships to disclose

Objectives

• Review the composition of blood & marrow HPC products for stem cell transplantation

• Discuss the management of patients undergoing infusion of HPC products

• Case-based presentations & discussion of infusion-related adverse events (AEs)

• Strategies to mitigate infusion-related AEs

2

HPC, Marrow Product

Infuse fresh

± manipulation ± cryopreservation

HPC, Marrow Product • Std volume goal: 10 – 15 mL/kg recipient wt• Std TNC goal: 2 – 4 x 108 TNC/kg recpt wt• Final HPC(M) Product

- Volume: 700 – 1500 mL (adult recipient)

- TNC count: 22 – 32 x 109/L (0.5 – 1% CD34+)

- TNC content: ~ 15 – 40 x 109

- Hematocrit: 20 - 30% - RBC vol: 180 - 380 mL

- Final anticoagulant/Buffer: Heparin 10 units/mL

in 10% Normosol-R or Plasma-Lyte A or ACD-A

HPC, Apheresis ProductMobilization w/ chemoRx &/or G-CSF ± plerixafor

Infuse fresh

Cryopreserve thaw/infuse

http//www.bloodca

3

HPC, Apheresis Product • Blood vol. process: 3x – 6x TBV (12 – 36 L)

• Std CD34+ goal: 2 - 5 x 106 /kg recpt wt/Txpl*

• Final HPC(A) Product** (for 12 L bld vol. process)

- Vol: 120 - 200 mL - Hct: 1 - 3% (2 - 6 mL RBC)

- TNC content**: ~ 15 – 70 x 109 CD34+: 0.2 – 1.5%

- MNCs**: 55 - 75% Granulocytes**: 25 – 55%

- Anticoagulant: ACD-A (6 - 8%) ± Heparin ~1 U/mL

• Cryoproduct: 10% DMSO + plasma or HSA + buffer

• Infusion: Thaw at bedside & infuse ASAP

HPC, Cord Blood Product

In Utero PlacentaHarvest

asherbenjamin.netjci.org

Ex utero or in utero harvest

into CPD(A)

Cryopreserve in5-10% DMSO ± dextran

http//www.taq.com

Thaw/dilute in labin dextran 40 + HSA

RBC-deplete*in HES andconcentrate

SCIENCEphotoLIBRARY*Some products RBC-replete

Infusion of Fresh HPC Products

Clinical Considerations*• Volume load: HPC(M) & peds

• ABO MM: Major w/ RBC > 20 mL;

Minor w/ plasma > 200 mL [titers]

• Hx transfusion Rxn: Pre-meds

• Heparin: aPTT; Hx of HIT(T)**

• ± Filter (institutional guideline)

• Monitoring: 15 min prior; q1hr during; for 2 hr post-infusion

*Sauer-Heilborn et al. Transfusion 2004;44:907

HPC product

**Heparin-induced thrombocytopenia (thrombosis)

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Infusion of Cryopreserved HPCsClinical Considerations*

• Post-thaw wash / dilute (UCB)

• Central venous access (for DMSO)

• DMSO: Dose 1 gm/kg (10 mL/kg)

– IV hydration: 2 hr pre 5 hr post

– Pre-meds: H1 blocker; antiemetics;hydrocortisone

• Dextran 40 (HES) (UCB)

• ± Filter (institutional guideline)

• Monitor: 15 min pre q15-30 min up to 4-24 hr post; *Emergency Meds*

*Sauer-Heilborn et al. Transfusion 2004;44:907

HPC product

Case 1: 23 yo with Aplastic Anemia• PMH: AA x 4 mo; o/w healthy

• Pre-Txpl: 80 kg; LVEF 69%

• Cond: Cytoxan, ATG, TBI

• URD HPC(M): ABO matched

– 30 hrs old – TNC 24.2 x 109

– 1200 mL infused over 8 hrs

• 4 hr post-infusion: SOB;

O2 sat’n 78% ICU/intubated;

EKG, troponin & BNP nl; PTT 39s

Case 1: Follow-up • Differential diagnosis

– TACO: Echo LVEF 65%; CVP 10

– Diffuse alveolar hemorrhage: Bronch / BAL (–)

– Sepsis/ARDS: Blood & BAL cultures (–)

– Product contamination: Gm stain (–); culture (P)

• Course: Resolved w/supportive care in 36 hr

– TRALI*: Pt sera (+) for non-HLA antibodies

*Urahama et al. Transfusion 2003;43:1553

SCCA HPC(M) AEs: 25% gr I-II; fever, N/V, hives, BP (peds)

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Culture-Positive HPC Products• Incidence: 0.2 – 26% (Recent: HPC(M) & HPC(A) ~1 – 7%)

• Higher rates: HPC(M) > HPC(A); manipulated products; LVL HPC(A)6 & pre-cryopreservation (vs post-thaw)

• Organisms: Coag (–) Staph > S. aureus > Bacillus, Corynebacterium, Propionibacterium

• Recipient Outcomes: No increase in infusion-related AEs; very rare 2o bacteremia or other clinical sequelae; no effect on engraftment or txpl course

• ± Prophylaxis for culture (+) cryo HPC product

1Kamble et al. Transfusion 2005;45:874 2Padley et al. Transfusion 2007;47:636 3Vanneaux et al. Cytotherapy 2007;9:508 4Klein et al. BBMT 2006;12:1142 5Patah et al. BMT 2007;40:365 6Donmez et al. Transfusion 2012;52:777

Case 2: 59 yo Relapsed B-Cell NHL

• PMH: Htn; CAD/pacemaker; DM

• Pre-Txpl: 87 kg; lung nodules

• Cond: Bu/VP-16/Ara-C/Melph

• Auto HPC(A): 2-days (22 bags)

• Day 1: 580 mL in 10 bags N/VBP; 2 hrs post-infusion CP, troponin NL, EKG: OK ( QTc !)

• Day 2: 10th bag (500mL) N/V; SOB & O2 satn severe CP

EKG: Anterior ischemia

Rapid deterioration to V-fib

Code Blue: Not resuscitated

Butler J M J Accid Emerg Med 2000;17:426

DMSO-Related Adverse Events

• Highly polar, permeable cryoprotectant

• Hyperosmolar (1800 mOsm) venotoxic

• Histamine-mediated AEs: 15 - 50%– Nausea/vomiting – Throat tickling – BP

– Cough – Flushing – Hiccup – Dyspnea

• Mitigation strategies– Antihistamines – Antiemetics

– Corticosteroids

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DMSO-Related Histamine AEs

Mitigation strategies– Aromatherapy

Ozdemir et al. BBMT 2008;14:1425

Potter et al. Cancer Nurs 2011;35:361 http://www.aromatherapy-regulation.org.uk/ICANHASCHEEZBURGER.COM

DMSO-Related Adverse EventsCardiovascular* / myocardial / vasogenic effects

– Tachycardia / bradycardia / heart block

– Hypertension / hypotension; creatinine

– Mild & transient; risk with AL amyloidosis

• Neurologic (usually transient & mild)

– Headache; LOC; amnesia; confusion; delirium

• Rare SAEs (? pathogenic mechanisms ?)

– Anaphylactoid – MI – Acute renal failure

– Encephalopathy, seizure, stroke (paradoxical embolism)

*Fitzhugh et al. Blood 2012;119:5671 – No difference in BP, TRV, creat w/ Cryo PBSC vs non-cryo

Does Removal of DMSO Reduce Infusion Related AE Incidence?

Adapted from: Windrum et al. BMT 2005;36:601

Survey of EBMT Transplant Centers

Per

cen

tag

e In

cid

ence

AE

s

All 5% DMSO 5–10% 10% Washed Not(n=95) (9) (6) (78) washed

*Adapted from: Sanchez-Salinas et al. Transfusion 2012; 8 Mar [Epub]

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Infusion Related AEs Are Related to Cryoproduct TNC/PMN Content*

*Calmels et al. Transfusion 2007;47:1268

n=10n=56

0

8

Med

. nu

mb

er P

MN

s (x

109 )

1 - 2 3 - 4

Prefreeze PMN content vs AE severity

28

58

n=55 n=10Med

. CD

45 v

iab

ility

(%

)

Post-thaw CD45 viability vs AE severity

0 1 - 2 3 - 4

71

48

58

412

• N = 460 No. infusions = 490 DMSO removed

• Gr 3 - 4 events: LOC; seizure; cardiac arrest

Case 2: 59 yo Relapsed B-Cell NHL• SAE: Myocardial ischemia V-fib arrest death

• Autopsy: Acute coronary thrombosis; severe CAD

• Other recent SCCA cases of infusion related SAEs

– 60 yo, refractory HL: Acute renal failure / dialysis

– 48 yo, plasma cell leukemia: Rapid multi-organ failure with death 30 hrs after infusion

Patient DMSO TNC/kg Gran/kg (%TNC)

Case 2 (NHL) 0.69 gm/kg 3.75 x 109 2 x 109 (54%)

Hodgkin lymphoma 0.78 gm/kg 3.05 x 109 2.3 x 109 (65%)

Plasma cell leukemia 0.95 gm/kg 6.14 x 109 4.6 x 109 (76%)

Patients InfusedQ1 Q4Q3Q2

Quartile Analyses of Cryo HPC(A) Infusions (n=411): TNC/kg vs AEs

Gr 3: Severe, requires interventionGr 4: Life-threateningGr 5: Fatal 1.63 x 109/kg

Quartile TNC/kg

Q2Q1 Q3 Q4

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SCCA Cryoproduct Infusion Policy Change to Limit TNC Dose

• New policy: Deliver 1.63 x 109 TNC/kg/day

• Implementation date: 12/4/2007

• 2010: Retrospective comparison from 18 mos pre-policy change (n=327) to 21 mos post-change (n=456)

– Infusion-related AEs frequency and severity

– Days of infusion

– Days to neutrophil engraftment

Cryo HPC(A) Infusion Days

(p<0.0001)

Pre-policy (n=327)

Post-policy (n=456)

Number of Days

% P

atie

nts

(M

ean

)

0102030405060708090

100

1 2 >2

7.9%0.6%

16.7%

5.8%

75.4%

93.6%

Khera et al. BBMT 2012;18:220

3 days: 24 pt4 days: 12 pt5 days: 1 pt

Product Content & Clinical Outcomes: Pre- vs Post-Policy Change

Parameter Pre-Policy (n=327)

Post-Policy (n=456) p value

Median CD34 x 106/kg/HCT (range)

6.38 (0.22 - 59.25)

6.33 (0.81 - 87.04)

NS

Median TNC x 109/kg/HCT (range)

0.87 (0.09 - 8.64)

0.87 (0.05 - 7.26)

NS

Median # infusion days

(range)

All HCTs 1 (1 - 4) 1 (1 - 5) NS

> 1.63 x 109 TNC/kg 1 (1 - 4) [n=82] 2 (1 - 5) [n=112] <0.0001

Median # days to neutrophil engraftment 14 14 NS

Infusions with grade 3 - 5 SAEs (%)

13(3.98%)

3(0.66%)

0.001

Khera et al. BBMT 2012;18:220

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Product Content & Clinical Outcomes: Pre- vs Post-Policy Change

Parameter Pre-Policy (n=327)

Post-Policy (n=456) p value

Median CD34 x 106/kg/HCT (range)

6.38 (0.22 - 59.25)

6.33 (0.81 - 87.04)

NS

Median TNC x 109/kg/HCT (range)

0.87 (0.09 - 8.64)

0.87 (0.05 - 7.26)

NS

Median # infusion days

(range)

All HCTs 1 (1 - 4) 1 (1 - 5) NS

> 1.63 x 109 TNC/kg 1 (1 - 4) [n=82] 2 (1 - 5) [n=112] <0.0001

Median # days to neutrophil engraftment 14 14 NS

Infusions with grade 3 - 5 SAEs (%)

13(3.98%)

3(0.66%)

0.001

Khera et al. BBMT 2012;18:220

Policy Change at SCCA• HPC(A) cryoproducts with high numbers of TNC

and granulocytes are associated with more frequent SAEs, including life-threatening events

• Limiting the dose of TNC/kg/day resulted in more multi-day infusions but without affecting kinetics of post transplant neutrophil engraftment

• Avoiding high daily TNC/kg dose infusions led to a significant reduction in grade 3 – 5 SAEs

Case 3: 15 yo Refractory NHL

• PMH: NHL; o/w healthy

• Pre-Txpl: 50 kg; febrile txf rxns

• Cond: Fludara / Cytoxan / TBI

• HPC(CB): 2 units; 5/6 Ag matches

• Bag #1: RBC depleted; thaw/dilute; 280 of 400 mL infused acute BP; SOB/wheezing; facial edema; hives

Actions: Epinephrine IM; IV fluids, IV hydrocortisone & diphenhydramine; bronchodilators

Anaphylaxis

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Case 3: Anaphylaxis w/ HPC(CB)

• Priority #1: Patient safety (Resp & CV status)

• Priority #2: BMT considerations (engraftment)– TNC received from bag #1? 2 x 107/kg

– Bag #2: RBC replete thaw/wash; 3 x 107 TNC/kg

• What in bag #1 caused anaphylaxis?– Plasma Ag – DMSO – Dextran 40 – Cell debris

• Can we “wash” bag #2 & infuse safely? – TNC recovery? – Remove offending agent?

Infusion AEs w/ HPC(CB) • Thaw & infuse (1 unit)

17% mild AEs1: BP, dyspnea

9% non-CV AEs2; – But 30 – 64% or BP, bradycardia

• Thaw & wash (mild & transient) 10% with 1 unit1: BP, dyspnea, fever

40% with 1 of 2 units3: BP, N/V, tingling

• Thaw & dilute (mild & transient) 10% with 1 unit 1: BP, bradycardia, N/V, dyspnea

65% with 1 of 2 units4: BP >> N/V, bradycardia

1Regan et al. Transfusion 2010;50:2670 2Konuma et al. BMT 2008;41:861 3Barker et al. Blood 2005;105:1343 4Barker et al. BBMT 2009;15:1596

SAEs w/ HPC(CB) Infusions • Concern with RBC replete units (> 20 mL RBC)

– Hemolysate*: Free Hgb, stroma, RBC membranes

– Bradycardia & hemoglobinuria (similar to auto BM1)

• “Stunned heart” syndrome2-5 [RBC replete >> depleted]

– Acute cardiopulmonary decompensation [CHF]

– Chest pain, BP, O2, N/V; troponin, LVEF; creatinine

– Usually reversible w/supportive care

• Anaphylactic(toid) reactions2,5 [RBC-depleted units]

• ? Mechanism ?: DMSO, hemolysate, Dextran 40 (anaphylaxis)

– Dextran sensitivity: ? IV test dose ? Dextran 1 prophylaxis6

1BMT 1999;23:533 2Acta Haematol 2009;122:1 3Miller. BB-IND #7555 Safety Report. NMDP:July 2009 4Am J Hematol 2010;85:722 5Transfusion 2012;52:207 6J Vasc Surg 2006;43:1004 *Fitzhugh et al. Blood 2012;119:5671

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Case 3: Anaphylaxis w/ HPC(CB)• Patient signs & symptoms resolved w/in 4 hr• What did we do with bag #2 ???

– Already thawed/washed: ~ 60 mL + dextran 40

– Manual “wash” x2 w/ 250 mL Normosol-R + HSA

– TNC recovery post-wash: 1.8 x 107/kg

– TNC viability post-wash: 75%

• Pre-meds: w/ diphenhydramine; HC; H2-blocker

• Infusion: ‘Test dose’ slow infusion in ICU

• Success! No reaction/sequelae; engraftment d22

Summary: HPC Infusion AEs

• Product cellular &/or solute constituents can trigger acute or delayed AE signs/symptoms

• Cryopreserved HPCs have unique risks/AEs

• Experienced personnel must plan, supervise & monitor HPC infusions & treat AEs

• Prophylactic & mitigation strategies must be utilized on a routine & patient-specific basis

• Further measures sought to optimize safety