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PresentationHandouts
(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 [email protected] Disclosures: No
Speaker Michael Linenberger, MD Medical Director, Apheresis & Cellular Therapy Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance [email protected] Disclosures: Yes
Speaker Olive Sturtevant, MHP, MT(ASCP)SBB, SLS, CQA(ASQ) Quality Assurance Director Dana Farber Cancer Institute [email protected] 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
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