Stem-Cell Transplant & MRD

1. Why Transplant?

Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) is the cornerstone curative therapy for high-risk haematological malignancies. Three mechanistic levers are simultaneously deployed:

• High-dose cytotoxic / radiation conditioning — eradicates leukaemia cells beyond the dose limits of conventional chemotherapy.
• Replacement of marrow — donor HSCs reconstitute haematopoiesis after the conditioning regimen has destroyed it.
• Graft-versus-leukaemia (GvL) effect — the donor immune system recognises and eliminates residual host leukaemia cells; the most powerful immunotherapy in routine clinical use.

Indications for allo-HSCT in CR1 in 2025:

• AML — ELN intermediate or adverse risk in fit patients with a donor; MRD+ after consolidation; secondary/therapy-related AML.
• ALL — high-risk cytogenetics (KMT2A, hypodiploidy, Ph-like), persistent MRD; T-ALL with poor early response; many adult ALL beyond the AYA group.
• CML — failure of multiple TKIs; advanced phase (AP, BP) after re-induction.
• CLL — rare in modern era; reserved for Richter transformation, refractory disease post-BTKi/venetoclax/CAR-T.
• MDS — high-risk MDS in fit patients; intermediate-2 / IPSS-R high or very high.
• Inherited bone-marrow failure — Fanconi, dyskeratosis congenita, severe congenital neutropenia.
• Severe aplastic anaemia — matched-sibling allo first-line in young patients.

Globally, ~85,000 HSCTs are performed each year (EBMT/CIBMTR registry data); about 60% are autologous (predominantly for myeloma and lymphoma), 40% allogeneic (predominantly for AML, ALL, MDS).

2. Autologous vs Allogeneic

Syngeneic transplants from an identical twin are vanishingly rare and behave as a cross between auto and allo (same MHC, but distinct minor antigens absent → no GvL).

3. HLA Matching

HLA (human leukocyte antigen) matching is the central determinant of allo-HSCT outcome. Six classical loci are typed at high resolution (allele-level) by sequence-based typing or NGS:

• Class I: HLA-A, HLA-B, HLA-C — expressed on all nucleated cells; present peptide to CD8 T-cells.
• Class II: HLA-DRB1, HLA-DQB1, HLA-DPB1 — expressed on professional APCs and B-cells; present peptide to CD4 T-cells.

Modern practice quotes a match as “n/8” (HLA-A, B, C, DRB1) or “n/10” (adding DQB1) or “n/12” (adding DPB1). The hierarchy:

Each single-allele mismatch increases acute GvHD by ~10% and TRM by ~4–5%. NMDP / Be The Match registry holds >40 million volunteer donors worldwide and a quarter-million cord-blood units. Donor diversity remains a major equity issue: minority populations have substantially worse MUD-matching probabilities than Caucasian populations of European descent.

4. Donor Sources of HSCs

Three sources, with different cell composition and engraftment kinetics:

The cell-dose threshold matters. Below ~2×10⁶ CD34/kg, engraftment is delayed and graft failure increases. Cord-blood transplants accept this risk in exchange for tolerance of HLA mismatch.

5. Conditioning Regimens

The conditioning regimen serves three purposes simultaneously: eradicate residual leukaemia, suppress recipient immunity to permit engraftment, and create marrow space for incoming donor cells. Two intensity classes:

The BMT-CTN 0901 trial (Scott, JCO 2017) randomised AML/MDS patients to MAC vs RIC and was stopped early for higher relapse in the RIC arm (48% vs 14%). Conclusion: in fit patients, prefer myeloablative; RIC is for those who can’t tolerate it.

Risk-score frameworks (EBMT, HCT-CI) capture the combined effect of multiple factors:

$$\;\text{Risk score} = f(\text{age},\;\text{disease stage},\;\text{donor},\;\text{interval},\;\text{sex match})\,.\;$$

6. Engraftment & Recovery

The transplant timeline:

• Day −7 to −1 — conditioning. Patient develops neutropenia, mucositis, nausea, alopecia.
• Day 0 — HSC infusion (intravenous “bag of cells”).
• Days +1 to +14 — pancytopenic; high infection risk; mucositis at peak. Antibacterial, antifungal, antiviral prophylaxis.
• Days +14 to +21 — neutrophil engraftment (ANC ≥0.5×10⁹/L for 3 days). Faster with PBSC, slower with cord.
• Days +20 to +35 — platelet engraftment (≥20–50×10⁹/L without transfusion).
• Days +30 to +90 — immunosuppression for GvHD prophylaxis (cyclosporine/tacrolimus + methotrexate, or post-transplant cyclophosphamide on days +3 and +4 for haploidentical).
• Day +100 marrow — documents engraftment, donor chimerism, MRD assessment.
• Months 3–12 — immune reconstitution; risk of viral reactivation (CMV, EBV, adenovirus, BK). Long-term tapering of immunosuppression.
• Year 1+ — chronic GvHD risk; revaccination; long-term surveillance.

Chimerism measurement — the fraction of recipient peripheral blood that is donor-derived — is performed by short-tandem-repeat (STR) genotyping or by NGS. Full donor chimerism (≥95%) is the expected end-point. Mixed chimerism predicts relapse and is sometimes managed with donor-lymphocyte infusion (DLI).

7. Graft-versus-Host Disease and Graft-versus-Leukaemia

GvHD is the central problem of allo-HSCT — the same alloreactivity that produces GvL also damages host tissues. Two clinical syndromes:

GvHD prophylaxis historically: calcineurin inhibitor (cyclosporine or tacrolimus) + methotrexate. Modern alternatives:

• Post-transplant cyclophosphamide (PTCy) on days +3 and +4 — selectively eliminates alloreactive proliferating T-cells while sparing regulatory T-cells. Originally for haplo-HSCT; now also used in matched donors (BMT-CTN 1703 trial: PTCy + tacrolimus + MMF beat tacrolimus + MTX for GRFS).
• ATG (anti-thymocyte globulin) — in vivo T-cell depletion; standard in many European protocols.
• Abatacept — CTLA4-Ig; FDA-approved for paediatric and adult HSCT GvHD prevention (ABA2 trial).

Graft-versus-leukaemia (GvL) is the therapeutic flip side: donor T-cells and NK-cells recognise minor histocompatibility antigens (and sometimes leukaemia-specific antigens) on residual leukaemic blasts and eliminate them. The classic demonstration is donor-lymphocyte infusion (DLI)for relapsed CML in chronic phase, which can re-induce molecular remission in ~70–80% — often the cleanest immunotherapy result in oncology.

8. Post-Transplant Complications

Beyond GvHD, allo-HSCT carries a long list of complications:

• Infections. Bacterial in early neutropenia. CMV reactivation in ~50% (letermovir prophylaxis since 2017 has reduced disease). EBV-driven post-transplant lymphoproliferative disorder (PTLD); rituximab pre-emptive. Adenovirus, BK, HHV-6 reactivations. Fungal — Aspergillus, Candida, mucormycosis. Pneumocystis prophylaxis with TMP-SMX.
• Sinusoidal obstruction syndrome (SOS) / VOD. Conditioning- or inotuzumab-induced injury to hepatic sinusoids. Tender hepatomegaly, jaundice, weight gain, ascites. Treated with defibrotide.
• Idiopathic pneumonia syndrome / DAH. Non-infectious lung injury within first 100 days; high mortality.
• Transplant-associated thrombotic microangiopathy (TA-TMA). Endothelial damage, complement-driven; eculizumab in severe cases.
• Engraftment failure. Primary (no recovery) or secondary (loss of graft); managed with second transplant.
• Secondary malignancies. Skin cancers, oral SCC, MDS/AML in donor cells (rare), solid tumours after TBI.
• Late effects. Endocrine (hypothyroidism, growth retardation, infertility), cataracts, osteoporosis, cardiovascular, neurocognitive (especially in children with TBI).
• Relapse. Despite all this, the leading cause of late mortality after allo-HSCT for AML remains relapse (~30%).

TRM (transplant-related mortality) at 100 days has fallen from ~20–30% in the 1990s to ~5–10% in the 2020s with modern donor matching, conditioning, and supportive care.

9. MRD as Endpoint — the Future

MRD at multiple time-points has become the dominant predictor of post-transplant outcomes:

• Pre-transplant MRD — MRD-negative pre-transplant patients have ~3-fold lower relapse than MRD-positive. The Buckley study (Blood 2017) and Walter (JCO 2017) showed MRD+ pre-transplant outcomes approach those of patients transplanted with overt residual disease.
• Day +100 MRD — persistence indicates failure of GvL to clear residual leukaemia; pre-emptive intervention (DLI, hypomethylating maintenance, FLT3 inhibitor) is increasingly used.
• Serial post-transplant MRD — rising chimerism loss or rising MRD precedes morphologic relapse by weeks to months; pre-emptive therapy is the goal.

Maintenance therapy after allo-HSCT has emerged for several settings:

• FLT3-mutant AML — sorafenib (SORMAIN trial, Burchert JCO 2020), midostaurin, gilteritinib (MORPHO trial 2024).
• High-risk AML/MDS — oral azacitidine (CC-486) maintenance (QUAZAR-AML-001, Wei NEJM 2020 — though chemotherapy not transplant maintenance).
• Ph+ ALL — TKI maintenance for ~1–2 years post-transplant, especially with detectable BCR-ABL transcripts.

CML and operational cure. CML patients in MR4.5 for >2 years on TKI may attempt treatment-free remission (TFR); ~50% maintain MMR off therapy at 3 years. This is the closest haematology has come to non-transplant cure of a leukaemia at scale (STIM, EURO-SKI, A-STIM trials), and is the model for what MRD-guided therapy could become elsewhere.

The overall message: MRD is the new endpoint — the metric that tells us whether a leukaemia has been cured, will relapse, or sits at the threshold. The haematology-oncology of the next decade will be increasingly built around MRD measurements at all the canonical time-points: end-of-induction, consolidation, pre- and post-transplant, and during long-term follow-up.

We close the course where it began: leukaemia is the cancer that has driven cancer biology and oncology forward more than any other — from the Philadelphia chromosome to imatinib, ibrutinib, venetoclax, and CAR-T. The same is likely to continue. Cross-references: Cancer, Cancer / genetic basis, DNA repair, Cancer therapy, Pharmacology, Cell Physiology.