Olive J Sturtevant, MHP, MT(ASCP)SBB/SLS, CQA Director, Cellular Therapy Quality Assurance Dana Farber Cancer Institute

Transcription

1 Adverse Events associated with Cell Therapy Products Olive J Sturtevant, MHP, MT(ASCP)SBB/SLS, CQA Director, Cellular Therapy Quality Assurance Dana Farber Cancer Institute

2 2 Objectives Review the types of Reactions and Adverse Events associated with various Cellular l Products and their additives & how we capture data Discuss some unique case studies of Adverse Events Identify process changes to help mitigate the symptoms and/or reduce the frequency of reactions Discuss the lack of consensus on reaction workup or review

3 3 What Is the true rate? DOCUMENTATION REACTION NOTED JUST SIGNS & SYMPTOMS RPT NO NFO 60 7 YES 123 NA # INFUSIONS RATE BASED ON UNEXPECTED ADE % 4/1210 RATE BASED ON RX YES 10.2% 123/1210 RATE BASED ON RX YES AND S&S 14.6% 177/1210

4 CIBMTR Form 2600 rev2 4

5 5 Reactions to Cell Therapy Products Mild (7% - 50%) Expected Febrile, Allergic, Volume Overload, DMSO Severe S 0.04% 04% (5/1410) Unanticipated Neurologic, Leukostatic, Anaphylactic, Cardiac

6 Reactions Based on HPC Product Types 21% reaction rate to autologous products 96% of the reactions are related to DMSO 2% Febrile 6 15% reaction rate to allogeneic products ABO compatible 13% ABO incompatible 22% 64% Febrile 17% Allergic

7 7 Reaction Types Febrile Allergic / Anaphalytic Hemolytic Cardiovascular / CHF Pulmonary / SOB, Coughing Volume overload TRALI / TACO Embolic Events / Stroke Sepsis bacterial contamination Other

8 Symptoms Frequently Reported 8 #Infusions # RX Symptoms Reported Nausea 82 7% 46% Vomiting 49 4% 28% Abdominal Pain 2 0% 1% Chills 19 2% 11% Fever 5 0% 3% Rash / Hives 7 1% 4% Flushing 31 3% 18% SOB/Coughing/Dyspnea 21 2% 12% Chest Tightness 3 0% 2% Jittery Legs 4 0% 2% Hematuria 0 0% 0% Other 84 7% 47%

9 9 WHAT S IN THE BAG? HPC (Cord, Marrow, Apheresis) TC - Cardiac, MSC, Tumor, CTL, Islets, etc Additives (buffer, HSA, FBS, etc) DMSO Cellular debris Other Additives Anticoagulants Hetastarch Ficoll DNAse Cytokines Antibiotics Study additives

10 10 Cellular Content

11 11 DMSO- Dimethyl Sulfoxide 7.5% or 10% DMSO used as a cryoprotectant The daily administration of <l g/kg of DMSO 96% of reactions to Auto HPC products are related to DMSO Symptoms: Strong associations to amount of cryopreserved granulocytes GI, Respiratory Epileptic seizure Skin reaction and breath odor (garlic) Systemic Side Effects of DMSO include some sedative headache, nausea, and dizziness

12 12 DMSO Rx and TIA o o Patient with Hodgkin Lymphoma underwent Autologous SCT During the infusion of the HPC-A, patient developed symptoms of Facial Droop, Numbness, Embolic dysarthria o Patient s symptoms resolved within minutes from the TIA (transient ischemic attack) o o Patient was scanned for brain mass, hemorrhage, clots, Carotids were scanned and a bubble ECHO performed o o o No clots, bleeds or masses seen. Carotids were unremarkable for arteriolosclerosis Bubble study revealed patent foramen ovale

13 13 Bacterial Contamination Incidence of contamination HPC-A 1.2 % to 1.6% Contaminating organisms Skin flora (SCN, P acnes) Line or blood (SCN, Salmonella ) Reaction Symptoms: Fever, rigors, tachypnea, chest pain, hyper /hypotension decreased urine output, DIC, renal failure, death Impact on outcome None to death

14 14 ADE with Contaminated Marrow BMT on a young male with CML Half way through infusion Patient developed fever, rigors Patient progressed to DIC and renal failure Sterility cultures positive approximately the same time patient first exhibited symptoms (4 hours ) Grams stain - GPRods (ID - B cereus)

15 15 Hemolytic Events Incidence is low Immediate: Immunological Fever, back pain, dark urine, dyspnea, chest pain, nausea and vomiting Anemia, increased LFTs Free Hemoglobin

16 16 ABO Incompatible Transplants Occurrence - ~20% Major ABO incompatibility RBC reduction if Recipients titer >1:16 Or if RBC volume equals? Practice ml of RBC in 24 hour period Minor ABO incompatibility Plasma reduction if donor plasma titer > 1:128 Or if volume is >125 ml

17 17 ADE due to Free Hemoglobin In two cases with ABO-identical grafts, infusion of free hemoglobin contributed t to clinical i l manifestations ti of a hemolytic reaction: hemoglobinuria, back pain, chest pain, nausea, and vomiting. Case 1, an ABO-identical cryopreserved HPC-A product Product contained 55 ml of hemolyzed red cells Case 2, an ABO-identical fresh unit of HPC-M with prolonged time from harvest to infusion Product contained 478 ml of hemolyzed red cells. Following onset of symptoms, the product infusion was halted. The remaining product was returned and washed Product was subsequently infused without further symptoms.

18 18 Febrile Non Hemolytic Temperature rise 1C Fever mild to severe Non-hemolytic febrile reactions are thought to stem from the release of cytokines during storage Leukoagglutinins or platelet agglutinins Seldom proceeds to hypotension or respiratory distress

19 19 Allergic Reactions Reactions can be mild or severe. Seen in 3% of Allogeneic Infusions Accounts for 17% of Allogeneic Symptoms can include: Hives, rash, flushing Anxiety Chest and/or back pain Trouble breathing Fever, chills, flushing, and clammy skin A quick pulse or low blood pressure Nausea Anaphylactic

20 Infusion Record 20

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22 22 Reaction Work-up Not standard across centers Range is from no workup to a serological workup similar to a blood reaction (DAT, ABO, etc.) Unit Gram stain and culture Endotoxin HLA? Recipient Culture, DAT, free hemoglobin, UA, DIC workup, LFTs Scans

23 Reduce Reactions Reduce RBCs in both fresh and cryopreserved products Reduce cellular debris (granulocytes, platelets, etc) Reduce R d removed unnecessary additives (DMSO, Albumin, FBS, etc) 23

24 Thank you & Questions 24