Transfusion medicine

Immunotherapy

Cellular therapy reactions



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PubMed Search: Cellular therapy reactions

Isabella M. Holmes, D.O.
Laura Cooling, M.D.
Page views in 2024 to date: 40
Cite this page: Holmes IM, Cooling L. Cellular therapy reactions. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transmedcellulartherapyreactions.html. Accessed April 14th, 2024.
Definition / general
  • Infusion of hematopoietic progenitor cells (HPCs) can cause a range of reactions from transient and self limiting to severe, regardless of HPC origin (i.e., marrow versus peripheral blood versus cord blood)
  • Therefore, it is important to acknowledge that these infusions are actually transfusions and all the components that make up the product have the potential to cause an adverse reaction in the recipient
  • Reference: Kopko: Transfusion Reactions, 5th Edition, 2021
Essential features
  • Infusion reactions related to cellular therapy infusion can occur with either cryopreserved or fresh HPCs
  • Acute reactions can occur during or within 12 hours after infusion with HPCs; additional delayed reactions (days) are expected for haploidentical hematopoietic stem cell transplants (HSCT) and chimeric antigen T cell receptor (CAR T) cell therapies
  • Reactions are more common with cryopreserved HPC due to both cryoprotectant, cell debris and passive infusion of inflammatory mediators; signs and symptoms attributed to cryopreserved HPC can overlap classic transfusion reactions
  • Reactions with fresh HPC (e.g., bone marrow) are similar to other blood components including allergic reactions and volume overload
  • Reference: Kopko: Transfusion Reactions, 5th Edition, 2021
Terminology
  • Hematopoietic progenitor cells (HPCs), HPC(M) = marrow, HPC(C) = cord blood, HPC(A) = peripheral blood by apheresis
  • Hematopoietic stem cell transplant (HSCT)
  • Cytokine release syndrome (CRS)
  • Reference: Kopko: Transfusion Reactions, 5th Edition, 2021
Pathophysiology
  • Cryoprotectant
    • Dimethyl sulfoxide (DMSO) is the most common cryoprotectant used for cellular therapy products, usually at a 10% final vol/vol concentration; HPC(C) and many CAR T may include dextran as well (Bone Marrow Transplant 1993;11:389)
    • Autologous peripheral blood HPC (HPC[A]) and cord blood HPC (HPC[C]) are always cryopreserved; bone marrow HPC (HPC[M]) is not typically frozen due to high red blood cell (RBC) content
    • DMSO
      • Is oncotic, leading to hyperosmolality and volume expansion, hypertension, headache, bradycardia
      • Can cause histamine release with flushing, cough, hypoxia, hypotension, arrhythmias
      • Can cross the blood - brain barrier with sedation, dizziness, encephalopathy, seizures
      • Is toxic and can cause nausea, vomiting, hepatic transaminitis, elevated creatinine kinase, intravascular hemolysis
    • Infusion toxicity is proportional to the total volume of DMSO infused (Biol Blood Marrow Transplant 2012;18:220)
      • Small pediatric patients, patients with renal insufficiency or amyloidosis are at increased risk for toxicity
      • Total DMSO should not exceed 1 gm DMSO/kg patient weight per day
    • DMSO is excreted as DMSO and dimethylsulfone (DMSO2) by kidney and as dimethylsulfide (DMSH2) by lungs; DMSH2 is responsible for the garlic aftertaste, halitosis, body odor and nausea in many patients
    • Dextran used in HPC(C) and other non-HPC cellular therapy products can cause anaphylactic reactions
  • Freezing related cell damage
    • Unlike mononuclear cells (HPC, lymphocytes, monocytes), granulocytes and red cells do not survive standard DMSO cryopreservation, resulting in cell lysis
    • Granulocytes
      • Granulocyte colony stimulating factor (G CSF) mobilized HPC(A) have high levels of activated neutrophils; infusion toxicity has been linked to a high prefreeze granulocyte dose
      • Lysis of G CSF activated granulocytes leads to passive infusion of WBC derived inflammatory cytokines and chemokines, apoptotic cells and cell debris
      • Severe reactions can occur at doses > 5 x 109 total granulocytes (Biol Blood Marrow Transplant 2012;18:220)
    • Red cells (Bone Marrow Transplant 1990;5:25, Bone Marrow Transplant 1999;23:533)
      • HPC(C) and HPC(M) contain significant RBC quantities: HPC(A) contain < 5 mL RBC
      • Toxicity attributed to infusion of free hemoglobin and cell debris
      • HPC(C) are always cryopreserved and at risk for passive infusion of lysed RBC with high rates of cardiovascular toxicity
        • HPC(C) are now RBC depleted before freezing; however, older cord units still contain significant RBC quantities
  • Electrolyte disturbances (Nephrol Dial Transplant 2008;23:359)
    • Cryopreserved HPC products have very low Ca++ and high K+ concentrations upon thawing
      • Citrate anticoagulant binds free calcium
      • Cell lysis with released intracellular K+
    • Risk for localized cardiac electrolyte abnormalities with rapid intravenous (IV) push, central line infusion
    • Rarely change in peripheral blood electrolytes
  • T cell activation and expansion (Biol Blood Marrow Transplant 2012;18:220, Nat Med 2019;25:1341, J Immunother Cancer 2018;6:56)
    • Expected in haploidentical HSCT (1 - 2 days postinfusion) and CAR T cellular therapies (4 - 10 days)
    • T cell activation causes the release of interferon (IFN) gamma, which results in a cascade of proinflammatory reactions resulting in a cytokine storm or cytokine release syndrome (CRS); interleukin 6 is a major driver in CRS and a target of therapy
    • Presents as fever and can progress to hypoxia, hypotension, organ failure and death
  • Donor plasma
    • Allergic reactions, transfusion related acute lung injury (TRALI), ABO and other red cell alloantibodies
    • Volume expansion
  • Reference: Kopko: Transfusion Reactions, 5th Edition, 2021
Diagrams / tables

Table 1: Infusion toxicity by etiology
DMSO Cytokines RBC / hemoglobin Plasma Volume Citrate
Nausea / emesis X
Fever / chills X X X
Cough X X
Flushing X X
Shortness of breath, hypoxia X X X X X
Hypotension X X X
Hypertension X X X
Bradycardia X X
Arrythmia X X X X
Neurologic X X X
Gastrointestinal pain X X X
Clinical features
  • Patient monitoring (Blood 1990;75:781, Anticancer Res 1998;18:4705)
    • During and after transfusion
    • Vital signs every 5 - 10 minutes during the first infusion, every 30 minutes for 2 - 4 hours after
    • Electrocardiogram (ECG) before and after infusion to monitor cardiac toxicity
  • Volume overload (Biol Blood Marrow Transplant 2013;19:1152)
    • Pretransplant hydration, particularly with ABO incompatible HSCT to prevent renal injury
    • HPC(M) infusion: small pediatric patients are at particular risk
    • Infusion of multiple cryopreserved HPC(A) units due to saline hydration, total volume and DMSO infused with hyperosmolality and intravascular expansion
    • Underlying cardiac and renal insufficiency
  • Hemolysis (Bone Marrow Transplant 1990;5:25, Bone Marrow Transplant 1999;23:533)
    • Immune hemolysis (see ABO incompatible HSCT)
      • Hemolysis of donor red blood cells associated with ABO major incompatibility HPC(M)
      • Hemolysis of recipient red blood cells associated with ABO minor incompatibility HPC(A)
    • Passive infusion of lysed RBC in cryopreserved HPC(C) and HPC(M)
  • Allergic reactions (Transfus Med Rev 2018 Jun 1 [Epub ahead of print])
    • Typically mild, pruritis, rash
    • Increased risk in patients with a history of allergy, allergic transfusion reactions
    • Usually associated with allogeneic HPC(A) containing donor plasma
    • Severe allergic reaction 1:1400 rate (Transfusion 1998;38:30S)
    • Rare cases of anaphylaxis due to dextran in HPC(C)
  • Pulmonary / respiratory symptoms (Bone Marrow Transplant 1990;5:25, Transfusion 2017;57:1522)
    • Volume overload, especially with HPC(M) infusions
    • DMSO induced
      • Coughing, transient hypoxia
      • Decrease in forced vital capacity (> 15%)
      • Rare, respiratory depression
    • Severe allergic / anaphylaxis (rare)
    • Transfusion related acute lung injury (rare)
    • Diffuse alveolar hemorrhage (rare)
    • Cytokine release syndrome (see CRS below)
  • Cardiac toxicity (Blood 1990;75:781, Transfusion 1993;33:578)
    • Decreased pulse rate most common; atrioventricular (AV) block and arrhythmias also seen
    • Onset 1 - 12 hours postinfusion (Bone Marrow Transplant 1992;10:435, Bone Marrow Transplant 1994;13:789)
    • Increased risk for cardiac events with
      • Cryopreserved HPC(M) and older, red cell replete HPC(C) units
      • Amyloid patients at risk for severe cardiac events during and after infusion
  • Cytokine release syndrome (CRS)
  • Neurologic
    • Cryopreserved, DMSO related (Cytotherapy 1999;1:311)
      • Headache related to hyperosmolality, volume expansion, hypertension
      • Less common: seizures, reversible severe encephalopathy, hemorrhagic stroke, global transient amnesia
    • Immune effector cell associated neurotoxicity syndrome (ICANS) (Biol Blood Marrow Transplant 2019;25:625)
      • CAR T cell therapies (0 - 67% of patients) (J Immunother Cancer 2018;6:56)
      • Onset > 10 days postinfusion, duration of weeks
      • Often but not always associated with a history of CRS
      • Lethargy, tremor, difficulty writing, naming objects
      • Severe ICANS seen in 10% of patients
        • Global aphasia, depressed responsiveness, seizures, diffuse cerebral edema
  • Bacterial or fungal contamination
    • HPC(M) has the highest rate of bacterial contamination (PLoS One 2015;10:e0141152, Braz J Infect Dis 2015;19:571)
      • Multiple skin punctures during marrow harvest
      • Normal skin flora (e.g., Cutibacterium, S. epidermitidis)
    • HPC(C) are at risk for contamination by vaginal and enteric organisms, especially when collected ex vivo after vaginal delivery and delayed transport / processing of the delivered placenta (Transfusion 2012;52:1770)
    • HPC(A) has a low rate of bacterial or fungal contamination
      • Most are false positive cultures due to laboratory contamination during sample culturing
      • Donor derived contamination is rare and usually associated with HPC collection in autologous HPC donors with colonized central lines
  • Reference: Kopko: Transfusion Reactions, 5th Edition, 2021
Symptoms
  • Fresh, noncryopreserved HPC infusions (Bone Marrow Transplant 1990;5:25, Bone Marrow Transplant 1999;23:533, Transfus Med Rev 2018 Jun 1 [Epub ahead of print])
    • Infused by gravity similar to other blood products
    • Risk for transfusion reactions similar to other blood products
    • Lower rate of infusion reactions (~10% overall) compared to cryopreserved HPC
      • HPC(M): risk for hypertension, headache, volume overload due to product volume
      • ABO major incompatible HPC(M) at risk for hemolytic transfusion reactions
      • HPC(A): risk for allergic reactions, postinfusion fever (first 24 hours)
  • Cryopreserved HPC infusions (Anticancer Res 1998;18:4705)
    • Thawed at bedside, infused by IV push (10 mL/min)
    • Significant infusion toxicity, reaching > 70% in some studies
    • Common (> 10%)
      • Nausea, vomiting, abdominal pain
      • Hypertension, hypotension
      • Bradycardia
      • Coughing
    • Less common (< 10%)
      • Chest tightness, dyspnea
      • Fever, chills
      • Flushing
      • Neurologic
Blood donor screening
Blood donor testing
  • Donors undergo standard infectious disease testing at least 30 days prior to HPC collection
  • Infectious disease testing is repeated on the day of donation
Donor deferral
Laboratory
Case reports
  • 16 year old boy undergoes allogeneic hematopoietic cell transplantation (HCT) and experiences a severe infusion reaction due to dextran (Bone Marrow Transplant 2017;52:1051)
  • 52 year old man who experienced tonic clonic seizure within minutes after the initiation of DMSO cryopreserved autologous peripheral blood progenitor cell (PBPC) infusion (Cell Tissue Bank 2018;19:831)
  • 63 year old woman with multiple myeloma presented for autologous peripheral blood HSC collection (J Clin Apher 2022;37:316)
Cellular therapy reaction prevention strategies
  • Premedication options (Blood Adv 2020;4:3041, Transfusion 1991;31:521, Biol Blood Marrow Transplant 2008;14:1425)
    • Antihistamines (diphenhydramine, 50 mg or chlorphenamine, 10 mg)
    • Steroids (hydrocortisone, 250 mg or methylprednisolone, 20 mg)
    • Antipyretic, due to the frequency of fever and chills
    • Antiemetics
    • Strawberry lollipops, lemon drops and orange slices were reported to reduce nausea and vomiting by counteracting noxious taste due to DMSO
    • ABO incompatible, saline hydration to prevent acute renal failure (maintain urine output > 100 mL/hour)
    • Prophylactic antibiotic coverage
      • Culture positive products may need additional antibiotic coverage
  • Contamination / transfusion transmitted infection (Arch Pathol Lab Med 2003;127:e19)
    • Donors are screened for transfusion transmitted disease prior to and on day of donation
    • Donors are screened for active infection, possible bacteremia prior to HPC collection
      • HPC(M): some centers infuse clindamycin prophylactically to mitigate bacterial contamination associated with bone marrow harvest
    • HPC products are processed in monitored clean rooms following good tissue practices (GTP) and good manufacturing practices (GMP)
    • All HPC products are cultured for contamination (aerobic, anaerobic, fungal); products are cultured after collection as well as during and after final processing as required
    • During thawing of cryopreserved HPC, products are placed in sterile overwraps and thawed in sterile water bath
    • Most patients receive prophylactic antibiotic coverage; patients receiving known heavily contaminated HPCs should begin appropriate antibiotic prophylaxis 2 days before infusion
  • Change the HPC infusion rate (Bone Marrow Transplant 1993;11:389)
    • Cryopreserved HPCs are infused at 10 mL/minute
      • HPCs in 10% DMSO are viable up to 1 hour postthaw, permitting a slower infusion rate if necessary
      • Fresh, noncryopreserved HPC are infused by gravity drip at 3 - 4 mL/min with less infusion toxicity
  • Red cell, plasma volume reduction (Blood Transfus 2014;12:150)
    • RBC depletion required in ABO major incompatible HPC(M) HSCT to prevent hemolytic transfusion reactions
    • RBC depletion now required in HPC(C) products to prevent severe infusion toxicity
    • Plasma reduction can be used with
      • Can be used with ABO minor incompatibilities
      • For prevention of volume overload (i.e., large grafts, children)
      • Can result in fourfold decrease in allergic reactions
  • Reducing DMSO concentration (Bone Marrow Transplant 1993;11:389)
    • Divided infusion over 2 days
    • Freeze at higher cell concentrations
      • Reduce the number of units/DMSO volume infused
      • Average concentration is 1 x 108 cells/mL: increase to 5 - 7 x 108 cells/mL without affecting CD34 viability
    • Product wash postthaw
      • Pros: can remove DMSO, red cells and cellular debris
      • Cons: postthaw cells are fragile and osmotically challenged, loss of CD34+ cells
    • Dilution
      • Common method for thawing HPC(C)
      • Add albumin - dextran 40 solution to postthaw cells to a ratio of 1:2 to 1:3
        • Pros: increase in postthaw cell viability
        • Cons: reports have implicated dextran 40 with severe cardiopulmonary reactions
  • Reducing granulocyte toxicity (Biol Blood Marrow Transplant 2012;18:220)
    • Limit infused cell dose to < 1.63 x 109 cells/kg/day
      • Pros: reduces severe reactions by 85%
      • Cons: increases the number of required days for infusion
    • Optimize HPC collection
      • Minimize the number of apheresis procedures
      • Addition of plerixafor for poor mobilizers
  • Alternative freezing solutions (Transfusion 2004;44:245)
    • Freezing with reduced DMSO concentration at 5% with or without 6% hetastarch and 4% albumin at -80°C
    • Non-DMSO cryoprotectants (not yet commercially available)
  • CD34+ cell selection (Vox Sang 2008;95:70)
    • Pros: absence of any measurable toxicity
    • Cons: high costs, cell loss (up to 50%) and limited institutional availability
  • Reference: Kopko: Transfusion Reactions, 5th Edition, 2021
Differential diagnosis
  • Many signs and symptoms can overlap with the patient's underlying clinical condition(s)
  • Medication adverse effects
  • Nonblood product related infection
Board review style question #1
A 49 year old, 82.7 kg man with a medical history of multiple myeloma is admitted for an autologous hematopoietic stem cell transplant (HSCT) with cryopreserved, plasma reduced HPC(A). He was premedicated with 650 mg of Tylenol and 50 mg of intravenous (IV) Benadryl. He was infused with a total of 200 mL HPC(A) containing 9.1 x 106 CD34+ cells/kg, 6.9 x 108 MNC/kg and 20 mL dimethyl sulfoxide (DMSO). Shortly after the infusion, the patient began to experience headaches, facial flushing, coughing and difficulty taking deep breaths. The nurse slowed the infusion and the patient's symptoms improved. Vital signs before, during and after infusion are shown below. What was the most likely cause of the patient's reaction?

Before During After
Time 12:03 12:44 16:33
Temperature (Celsius) 36.5 36.5 37.1
Heart rate 92 97 86
Resp rate 16 20 16
Blood pressure 148/83 132/78 120/66
SpO2% 96 95 99
O2 device None (room air) None (room air) None (room air)

  1. Anxiety: psychological stress and anxiety surrounding the infusion
  2. DMSO toxicity from cryopreservation
  3. Severe allergic reaction without anaphylaxis due to plasma
  4. Volume overload: due to rapidly increasing intravascular volume
Board review style answer #1
B. DMSO toxicity from cryopreservation. The patient began to have difficulty with deep breaths, flushing, coughing and headaches shortly after his infusion began. This patient was experiencing a classic reaction to DMSO. DMSO can cause a wide array of reactions including headache, nausea, dizziness, halitosis, hypoxia, chest tightness, coughing and hypotension. DMSO is hyperosmolar with expansion of intravascular volume and capable of inducing histamine release with flushing, coughing, chest tightness or dyspnea. Answer A is incorrect because the question stem does not mention any signs or symptoms specifically related to anxiety. In addition, he was premedicated with 50 mg IV Benadryl, which is very sedating; however, it is paramount to keep a broad differential diagnosis when assessing patients with possible reactions to infusion of any products. Answer C is incorrect because a severe allergic reaction is unlikely since this was plasma reduced and autologous stem cells. Answer D is incorrect because a volume overload is unlikely since the infusion was only (2 units - 200 mL). One strategy to reduce reactions due to infusion includes slowing the rate (Kopko: Transfusion Reactions, 5th Edition, 2021).

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Reference: Cellular therapy reactions
Board review style question #2
A 19 year old, O+ blood type, 52.1 kg woman with acute myeloid leukemia (AML) was admitted for a matched (8/8), unrelated, allogeneic ABO incompatible HPC(M) bone marrow transplant from a group A+ donor. The original marrow volume was exceptionally large (1,694 mL) and bloody (Hct = 30%). After red cell and plasma depletion, the processed marrow was 390 mL with 164.6 mL residual donor red blood cells (RBC) and a total cell loss of 8% for a final yield of 3.1 x 106 CD34 cells/kg. The patient was premedicated with Tylenol 500 mg PO, intravenous (IV) Solu-Cortef 100 mg and IV diphenhydramine 50 mg. HPC(M) was infused by gravity flow at 3 - 4 mL/minute. During infusion, the patient developed headaches that did not resolve with Tylenol. Toward the end of the transplant, her blood pressure rose from 123/74 to 152/92. Hydralazine and magnesium boluses were ordered and blood pressure began to downtrend. Hemoglobinuria was noted after the completion of the transplant. What is the reaction this patient is experiencing and what is the most likely cause?

  1. Acute dimethyl sulfoxide (DMSO) toxicity: due to rate of infusion
  2. Adverse medication reaction: premedication with Solu-Cortef
  3. Dehydration: patient has not consumed any fluids since the procedure due to an upset stomach
  4. Immune hemolysis: due to major ABO incompatibility (A donor / O recipient)
Board review style answer #2
D. Immune hemolysis: due to major ABO incompatibility (A donor / O recipient). This patient is experiencing an acute hemolytic transfusion reaction due to infusion of ABO incompatible HPC(M) marrow transplant. HPC(M) are quite bloody and still contain significant red cells even after RBC depletion because of the need to balance depletion against CD34 cell losses. Her pretransplant anti-A IgG titer was 256 and anti-A IgM titer was 32. Her headache was caused by a dramatic increase in systolic blood pressure (123 → 154) because of excess volume from transplant and aggressive hydration to prevent acute kidney injury and nitric oxide scavenging with heme mediated vasoconstriction. Answer A is incorrect because she was not exposed to DMSO; the patient received an allogeneic marrow transplant, which is not cryopreserved and infused fresh. Answer B is incorrect because this patient would not have hemoglobinuria due to an adverse medication reaction to Solu-Cortef . Answer C is incorrect given hypertension, not hypotension (Kopko: Transfusion Reactions, 5th Edition, 2021).

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