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GRANULOCYTES

TRANSFUSION

Peter MacCallum Centre

Clinical Haematology

Derek Dinh, 2023

Basic Physiology

Granulocytes are cells in the innate immune system characterized by the presence of specific granules in their cytoplasm.

Granulocytes are produced from stem cells in the bone marrow and only live for a few days.

Components of Granulocytes

Roles Granulocytes

Neutrophils: predominant role in the clearance of

bacteria and fungi

shaping the host response to infection and immune system homeostasis (Malech, 2014)

Eosinophils: involved in host defense against parasites

and promoting allergic reactions

Innate immunity to adaptive immunity and also involves non-immune cells (Wen, 2016)

Basophils: the least abundant in the circulation

radily expand in the bone marrow in response to inflammatory signals (Min, 2012)

History of GTX

Buffy coat: oldest form of cell therapy - 1934

However, obtaining enough neutrophils from healthy donors to produce a measurable increase in absolute neutrophil count (ANC) was challenging - This prompted using as donors patients with chronic myelogenous leukemia, who had ANC of up to 300,000 /μL

History

1969 - Blood-flow separator - establish transfusion as a viable procedure

1972 - Case study published - favorable effect in neutropenic patients

1975-1982 - Some RCTs involving pts with bacterial infection

in neutropaenia

1981 - Significant toxicity - Lethal pulmonary reaction

Gea-Banacloche, 2017

Renewed interests

1993 - 2001 - availability of colony-stimulating factors (granulocyte colony-stimulating factor (G-CSF)

2001 - 2011 - reason for the negative results of some trials was insufficient dose - hence GCSF +/- Dexa increase the yield of granulocytes

1990s - minimal use in GTX

2012 - granulocytes may be obtained from the blood by centrifugation and collection of the “buffy coat” (the layer between the red cells and plasma) which results in a product rich in platelets and less abundant in granulocytes

Practical Considerations

Ideally, transfusion should take place less than 6 hours after collection.

Practical

It is customary to irradiate the cells before transfusion to prevent transfusion-associated graft versus host disease (TA-GVHD) due to lymphocytes.

However, some believes this compromises neutrophil function and unirradiated granulocytes can be employed safely.

A controlled trial of irradiated vs nonirradiated GTX did not find any difference and there were no cases of TA-GVHD (Freireich, 2013)

Donor Issues

Family members and friends: tend to be highly motivated and cooperative, but most of them have not donated blood before. It generally takes 2-3 days to undergo testing and screening of their blood, hence will delay the initiation of GTX

What else?

Community donors: time interval between the request for granulocytes and transfusion was significantly less in patients receiving granulocytes

Donor stimulation: GCSF in the evening - collect in the morning

Side-effects of GCSF +/- Dexa: mostly mild + short lasting effects

Burden on the donor: 3 trips to the donation centre (screening + testing, medication administration, and then donation 4-5hrs)

Minimum Criteria

Indication

Regardless of the cause of the patient's neutropenia:

- Absolute neutrophil count (ANC) < 500 cells/microL, except in the case of chronic granulomatous disease.

- Evidence of bacterial or fungal infection (ie, clinical symptoms of infection, positive cultures, pathological diagnosis of infection from biopsies, radiographic evidence of pneumonia).

- Unresponsiveness to antimicrobial treatment for at least 48 hours (except in extreme circumstances with life-threatening infection)

Clinical Applications

Chemotherapy or hematopoietic cell transplantation (HCT)-induced neutropenia — is the most common use of GTX, although the use of GTX in this population remains rare.

Multidrug-resistant bacterial infection and fungal infection in patients with neutropenia remain a major cause of morbidity and mortality.

Applications

The Resolving Infection in Neutropenia with Granulocytes (RING) trial was a randomized trial to address the efficacy of G-CSF-mobilized granulocytes in patients with neutropenia (ANC <500/microL) due to chemotherapy or HCT who had a proven or probable bacterial or fungal infection - End point: survival + antimicrobial responses at 6 weeks - no differences (Price, 2015)

Some observational studies before RING showed mixed results, with several suggesting a benefit of GTX in treatment of infection and/or survival.

Prophylactic GTX remains controversial due to the potential adverse effects of GTX, and we do not use GTX for infection prophylaxis outside of a clinical trial

GTX may be appropriate for patients with severe AA and neutropenia when bacterial or fungal infection is unresponsive to maximal antibiotic and/or antifungal therapy - A significant issue in the use of GTX for AA is the high incidence of HLA alloimmunization due to transfusions of RBCs and platelets, which can in turn increase the risk for transfusion-related acute lung injury (TRALI)

(Quillen, 2009)

A number of small studies and case reports have documented the success of GTX in treating patients with chronic granulomatous disease with invasive aspergillosis (Ozsahin, 1998; Bielorai, 2000)

Administration

Recipients of GTX should be monitored for changes in absolute neutrophil count (ANC) by monitoring daily morning white blood cell count and differential. The post-transfusion ANC increment can be quite large in patients receiving granulocytes from granulocyte colony stimulating factor (G-CSF)- and corticosteroid-stimulated donors

Transfused granulocytes have normal function in bactericidal, fungicidal, and chemotactic activities and are capable of migrating to extravascular sites and localizing to areas of infection

Administration

Criteria for stopping granulocyte transfusions:

- The clinical infection has been resolved based on clinical signs/symptoms, and laboratory/radiological test results.

- The patient's ANC is above 500 for three days without GTX, which is a sign of bone marrow recovery.

- The patient's clinical condition has worsened (ie, poor response to GTX), and the treatment plan has changed to palliative care with patient and family consent.

Complications

Moderate to severe pulmonary adverse reactions: cough, dyspnoea, hypoxia (< 5%) (Hester, 1995)

Alloimmunization - retrospective review: 17 percent of patients with severe aplastic anemia developed Human Leukocyte Antigen (HLA) antibodies during the course of GTX, and that patients with detectable HLA antibodies had lower post-GTX white blood cell increments (Quillen, 2009)

What about risks?

Transfusion-associated graft-versus-host disease

Transfusion-transmitted infections are just as important a consideration in GTX as with the use of any other blood transfusion, especially CMV, since CMV is harbored in peripheral blood leukocytes

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