Principles of transfusion and bone marrow transplantation

Autologous vs allogeneic - two completely different operations

	Autologous	Allogeneic
Graft	Patient's own mobilised stem cells	Donor cells
Purpose	Rescue from otherwise lethal high-dose chemotherapy	Replace the marrow + graft-versus-tumour immune effect
GVHD	None	The central problem
Relapse	Higher - no immune effect, possible graft contamination	Lower
Transplant-related mortality	~1-3%	~10-30%
Age ceiling	~70-75	~70 with reduced-intensity conditioning

*Autologous transplant is intensive chemotherapy. Allogeneic transplant is immunotherapy.*

Activity in Australia

~1,500 autologous and ~700 allogeneic transplants annually in Australia (ABMTRR)
Autologous - by volume: myeloma (the largest single indication) > non-Hodgkin lymphoma > Hodgkin lymphoma > germ cell and other solid tumours > selected autoimmune disease (scleroderma, multiple sclerosis, Crohn)
Allogeneic - by volume: AML (the largest) > ALL > NHL/MDS > myelofibrosis, aplastic anaemia, haemoglobinopathies, primary immunodeficiency
*Allogeneic transplant for CML has collapsed* since TKIs
Median age rising - reduced-intensity conditioning has opened transplant to patients in their 60s and 70s

Graft-versus-host disease - the three requirements (Billingham)

1. Immunocompetent donor T cells in the graft

2. Histocompatibility differences between donor and recipient

3. Recipient unable to reject the graft (immunosuppressed)

Acute GVHD mechanism - three phases

Phase 1 - conditioning damages host tissue -> cytokine storm (TNF, IL-1), gut mucosal injury -> LPS translocation, upregulated MHC and adhesion molecules
Phase 2 - host APCs present alloantigen -> donor T cell activation and clonal expansion (Th1)
Phase 3 - effector phase: CTLs, NK cells, TNF, IFN-gamma -> target organ damage
*Target organs: skin, gut, liver* (the interfaces with the environment)

Graft-versus-tumour

The same alloreactivity, redirected - donor T and NK cells recognising minor histocompatibility antigens on residual tumour
*Inseparable from GVHD: reducing GVHD increases relapse*
Evidence: lower relapse with GVHD, higher relapse in syngeneic and T-cell-depleted grafts, donor lymphocyte infusion can re-induce remission

Transfusion-associated GVHD

Transfusion-associated GVHD - the same biology by a different route

Viable donor T lymphocytes in a cellular blood product engraft in an immunocompromised recipient (or one sharing an HLA haplotype with the donor)
Attacks recipient marrow -> pancytopenia, >90% mortality
*Prevented definitively only by irradiation (25 Gy) of cellular products. Leucodepletion reduces but does not eliminate the risk*

Donor selection - in order of preference

1. HLA-matched sibling (~25-30% chance per sibling)

2. Matched unrelated donor - 10/10 at HLA-A, B, C, DRB1, DQB1

3. Haploidentical family donor - parent, child or sibling; now routine with post-transplant cyclophosphamide, and available for nearly everyone

4. Umbilical cord blood

Graft source	Pros	Cons
Peripheral blood stem cells (G-CSF mobilised, +/- plerixafor)	Faster engraftment (~day 12-14), no anaesthetic for donor	More chronic GVHD (more T cells)
Bone marrow harvest	Less chronic GVHD	Slower engraftment; general anaesthetic
Umbilical cord blood	Less stringent HLA matching, immediately available, rich in CD34+ cells with naive, less alloreactive T cells	Delayed engraftment (~day 20+), longer neutropenia and infection risk, 5-10% graft failure - cell dose limited by the size mismatch between the donation and an adult recipient

Also match for: CMV serostatus, ABO (not a barrier, but causes delayed red cell engraftment and haemolysis), sex (female donor to male recipient -> more GVHD), donor age (younger is better)

Conditioning

	Regimen examples	Purpose
Myeloablative	Cyclophosphamide-TBI, busulfan-cyclophosphamide, BEAM (autologous lymphoma), melphalan 200 mg/m2 (autologous myeloma)	Maximum tumour kill; irreversible marrow ablation
Reduced intensity / non-myeloablative	Fludarabine-melphalan, fludarabine-busulfan, flu-TBI 2 Gy	Immunosuppress enough to allow engraftment, then rely on graft-versus-tumour. Older/comorbid patients

Assessing fitness

HCT-CI (comorbidity index), performance status, disease status (remission at transplant is the strongest predictor of outcome)
Cardiac (echo), respiratory (lung function with DLCO), renal, hepatic
Infection screen - CMV, EBV, HSV, VZV, HIV, hepatitis B and C, toxoplasma, syphilis, strongyloides, TB
Dental review; fertility preservation discussion before conditioning

Indications - autologous

A. Indications - autologous

Multiple myeloma - consolidation after induction in transplant-eligible patients
Relapsed intermediate-grade NHL that is chemosensitive; incomplete response to primary NHL therapy
Relapsed Hodgkin lymphoma
Relapsed germ cell tumours; severe refractory autoimmune disease (scleroderma, MS, Crohn)
Primary CNS lymphoma consolidation

Indications - allogeneic

B. Indications - allogeneic

AML - adverse risk in CR1, or any AML in CR2
ALL - high risk in CR1, MRD-positive, relapsed
MDS with high IPSS-R/IPSS-M; myelofibrosis with high DIPSS
Severe aplastic anaemia (first-line in young patients with a matched sibling)
Sickle cell disease and thalassaemia major (though gene therapy is displacing this)
Primary immunodeficiency, inborn errors of metabolism
Relapsed/refractory lymphoma and CLL after other options

Timeline and its complications

C. Timeline and its complications

Phase	Timing	Problems
Pre-engraftment	Day 0 to ~+14-30	Neutropenic sepsis, mucositis, Candida, HSV, sinusoidal obstruction syndrome, engraftment syndrome
Early post-engraftment	~Day 30-100	Acute GVHD, CMV reactivation, PJP, Aspergillus, adenovirus, BK haemorrhagic cystitis
Late	>Day 100	Chronic GVHD, encapsulated organisms, VZV, PTLD (EBV), secondary malignancy, endocrine and gonadal failure

Engraftment: neutrophils >0.5 for 3 days - PBSC ~day 12-14, marrow ~day 18-21, cord ~day 20-30

GVHD prophylaxis and treatment

D. GVHD prophylaxis and treatment

Post-transplant cyclophosphamide (day +3, +4) + a calcineurin inhibitor +/- mycophenolate is now the standard backbone, across matched, mismatched and haploidentical donors
- It selectively deletes alloreactive T cells while sparing regulatory T cells and stem cells; it has markedly reduced chronic and fibrotic GVHD
Alternatives/additions: ciclosporin or tacrolimus + methotrexate, ATG, T-cell depletion (more relapse, more infection)

Acute GVHD (classically <100 days; graded I-IV by skin, gut, liver)

First line: high-dose corticosteroid (methylprednisolone 1-2 mg/kg) + continue calcineurin inhibitor
Steroid-refractory: ruxolitinib (REACH2) - the standard second line

Chronic GVHD (NIH consensus criteria; sclerodermatous skin, sicca, oral lichenoid change, bronchiolitis obliterans, fasciitis, cytopenias)

First line: corticosteroid +/- calcineurin inhibitor
Second line: ruxolitinib (REACH3) - now the preferred agent
Belumosudil (ROCK2) and axatilimab (anti-CSF1R) for refractory and fibrotic-predominant disease; extracorporeal photopheresis, rituximab, ibrutinib

Infection prophylaxis and vaccination

E. Infection prophylaxis and vaccination

Antifungal (posaconazole/voriconazole), antiviral aciclovir/valaciclovir, PJP prophylaxis co-trimoxazole, antibacterial in neutropenia
Letermovir for CMV prophylaxis in seropositive allogeneic recipients; otherwise weekly CMV PCR with pre-emptive valganciclovir
Revaccinate from ~6-12 months - the recipient loses all prior immunity. Live vaccines only after 24 months and off immunosuppression, with no GVHD
Lifelong penicillin prophylaxis if functional hyposplenism from chronic GVHD

Transfusion support in transplant

F. Transfusion support in transplant

*Irradiated cellular products from the time of stem cell harvest, and indefinitely after allogeneic transplant*
CMV-safe (leucodepleted) products
ABO-mismatched transplant: transfuse red cells compatible with both donor and recipient until the recipient's original isohaemagglutinins clear
Chimerism monitoring; DLI for falling donor chimerism or relapse

Complications

Graft-versus-host disease - acute and chronic
Sinusoidal obstruction syndrome (veno-occlusive disease) - weight gain, tender hepatomegaly, jaundice; defibrotide
CMV, EBV (PTLD), adenovirus, BK virus, HHV-6, invasive aspergillosis
Graft failure and poor graft function
Transfusion-associated GVHD (the reason for irradiation)
Secondary malignancy - MDS/AML after autologous transplant, skin and oral SCC after chronic GVHD
Endocrine: hypothyroidism, growth failure, infertility and premature ovarian insufficiency
Cataracts (TBI), avascular necrosis, osteoporosis
Post-transplant thrombotic microangiopathy (calcineurin inhibitors)
Iron overload from cumulative transfusion

Outcomes

Autologous: transplant-related mortality ~1-3%; myeloma - improves PFS, not curative
Allogeneic: transplant-related mortality ~10-30%, dominated by GVHD and infection
Disease status at transplant is the strongest predictor - transplant in remission, not in active relapse

Acute GVHD outcomes

Acute GVHD

~30-50% grade II-IV with conventional prophylaxis; substantially lower with post-transplant cyclophosphamide
Grade III-IV carries ~25% long-term survival

Chronic GVHD

~30-50% of long-term allogeneic survivors (lower with PTCy)
The leading cause of late non-relapse mortality and of impaired quality of life
Some chronic GVHD is protective against relapse - the graft-versus-tumour trade-off

Long-term survivorship

Lifelong follow-up required
Screen for: second cancers (annual skin and oral examination), cardiovascular risk, thyroid and gonadal function, bone density, cataracts, iron overload, respiratory function (bronchiolitis obliterans)
Psychological morbidity and fatigue are common and under-treated

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