Allogeneic stem cell transplantation (allo-HSCT)

Principle and Indications

• Goal: achieve a graft-versus-tumor (GVT) effect without excessive host organ injury. The graft must retain immunologically active cells, and the host must express alloantigens absent from the graft.
• AML in CR1: base transplant on integrated ELN 2022 genetic risk plus MRD. Allo-HCT favored for adverse-risk and most intermediate-risk disease; NPM1-mutated, FLT3-ITD-negative AML with MRD clearance generally does not require allo-HCT in CR1. EORTC/GIMEMA (Suciu S et al, Blood 2003): DFS favored allo over auto SCT in adverse cytogenetics (43.4% vs 18.4%). Meta-analysis: allo-HCT improved 5-year OS from 45% to 52% (intermediate-risk cytogenetics) and 20% to 31% (poor-risk); no benefit in good-risk.
• MDS: only curative option, but generally deferred in lower-risk disease (modeled survival favors delay), but consider in selected lower-risk patients with adverse molecular features, severe cytopenias, high transfusion burden, or HMA failure; high-risk MDS to HCT upfront.
• MRD-positive young AML: myeloablative conditioning favored (see conditioning below).

Donor Selection

• Hierarchy: matched sibling donor (MSD) > matched unrelated donor (MUD 10/10) ≈ haploidentical (PTCy) > mismatched UD > umbilical cord blood (UCB).
• HLA matching: HLA-A, B, C, DRB1, DQB1 (10 alleles); 8/8 (high resolution A/B/C/DRB1) is minimum for MUD.
• PTCy in haplo: Luznik regimen, post-transplant cyclophosphamide days +3, +4, eliminates alloreactive T cells. Equivalent or superior outcomes to MUD in some series.
• PTCy now standard for MUD: BMT-CTN 1703 (Bolanos-Meade J et al, NEJM 2023; PMID: 37342922), PTCy + tac + MMF SUPERIOR to tac/MTX after RIC with matched related, matched unrelated, or 7/8 mismatched unrelated donors: 1-yr GVHD-free relapse-free survival 52.7% vs 34.9% (HR 0.64, P=.001); OS not different. Now widely adopted; extends the Luznik haplo paradigm to MUD.
• UCB: fewer matching restrictions; slower engraftment; less GVHD; ↑ infection risk.
• Donor age: younger donors give better outcomes; matters more than HLA in some studies.
• CMV serostatus matching: the worst pairing is CMV-negative donor into CMV-positive recipient (D-/R+): on reactivation there is no donor-derived pre-existing immunity to transfer. A CMV+ donor can transfer a more robust anti-CMV response. Monitor CMV closely post-allo (reactivation causes hepatitis, pneumonia, retinitis, encephalitis).

Mobilization

• G-CSF (filgrastim): primary mobilizing agent driving CD34+ progenitors from marrow into peripheral blood for apheresis collection.
• Plerixafor: inhibits the CXCR4 chemokine receptor on CD34+ cells and reversibly blocks binding of its ligand, stromal cell-derived factor-1-alpha (SDF-1α). Disrupting the SDF-1α/CXCR4 interaction triggers release (mobilization) of progenitor cells; added to G-CSF for poor mobilizers.
• Target cell dose: CD34+ ≥ 2 × 10⁶/kg minimum; higher doses associated with better engraftment.

Conditioning Regimens

• Myeloablative (MAC): busulfan + cyclophosphamide (Bu/Cy), TBI + Cy, fludarabine + high-dose busulfan. For young fit patients; TBI-based preferred in ALL. In AML, MRD+/high-risk favors myeloablative intensity when tolerable, but busulfan-based MAC remains a standard backbone (TBI not specifically preferred).
• Reduced-intensity (RIC): Flu/Bu (low-dose busulfan), Flu/Mel. For older or comorbid patients; relies more on graft-vs-leukemia.
• Non-myeloablative (NMA): Flu/TBI 2 Gy, Flu/Cy; minimal toxicity, ↑ relapse risk.
• MAC vs RIC: Scott BL et al, JCO 2017 (BMT-CTN 0901, AML/MDS): RIC gave much higher relapse (48.3% vs 13.5%) and lower relapse-free survival (47.3% vs 67.8%) despite lower TRM (4.4% vs 15.8%); 18-month OS 67.7% vs 77.5% (P=.07). In the MRD substudy (Hourigan JCO 2020), MRD+ patients had more relapse (HR 6.38) and worse OS (HR 1.97; P=.01) with RIC, whereas MRD-negative patients had similar 3-yr OS (56% vs 63%). Choose MAC for younger fit patients (especially MRD+); RIC for older/comorbid.
• Conditioning backbone: Copelan EA et al, Blood 2013 (CIBMTR registry, AML in CR1): IV Bu/Cy vs Cy/TBI gave less non-relapse mortality, lower relapse after 1 year, and better leukemia-free survival and OS.
• Special, ALL: TBI-based conditioning standard (FORUM trial, TBI/etoposide superior in pediatric ALL).

• Busulfan cautions: start anticonvulsant prophylaxis before busulfan (seizure risk); increased hepatic veno-occlusive disease risk when the per-dose AUC exceeds 1,500 µM·min with every-6-hour dosing (target ~900 to 1,500 per 6-hour dose); interpret daily and once-daily targets accordingly; monitor transaminases, alkaline phosphatase, bilirubin daily; embryo-fetal toxicity (effective contraception).

Graft Sources

• PBSC vs BM: mobilized PBSC has faster engraftment but ↑ chronic GVHD (BMT-CTN 0201, survival similar in MUD setting; chronic GVHD higher with PBSC).
• UCB: lower GVHD but slower engraftment, ↑ TRM in some series; a single unit may give insufficient cell dose for a heavier recipient (cell dose is assessed per kg), though single-unit transplant is feasible when nucleated cell and CD34+ doses, HLA match, and unit quality are adequate. In a pediatric/young-adult study (n=224), single-unit vs double-unit UCB gave similar 1-yr OS (73% vs 65%, P=0.17) but single units had improved platelet recovery and lower incidence of grade III to IV acute and extensive chronic GVHD. Useful when no other donor is available.
• Cell dose: CD34+ ≥ 2 × 10⁶/kg minimum; higher associated with better engraftment.

Engraftment and Graft Failure

• Engraftment: ANC > 500 for 3 days (median day +14 to +21 PBSC, +21 to +28 BM, +25 to +40 UCB).
• Engraftment syndrome: febrile syndrome during early neutrophil recovery. Fever and skin rash are the two most common features; may also see pulmonary infiltrates/edema, weight gain, liver/renal dysfunction, encephalopathy, capillary leak. Driven by neutrophil recovery releasing proinflammatory cytokines (TNF, IL-1); post-transplant G-CSF increases its incidence. Steroids help. Distinguish from GVHD and infection.
• Post-transplant pure red cell aplasia (PRCA): recipient isohemagglutinins interfere with donor erythroid engraftment (major ABO mismatch). Reduced-intensity/reduced-toxicity regimens leave more host immunity and may affect PRCA incidence.
• Passenger lymphocyte syndrome: immune hemolysis after a minor ABO-mismatched graft. Viable donor B lymphocytes (often from a female donor) transferred with the graft produce antibodies (eg, anti-A) against recipient red cell antigens, causing hemolysis several days to weeks post-transplant; Lewis and Rh systems can also be involved.

Complications by Transplant Phase

Mucositis, VOD/SOS, and TA-TMA

• Mucositis: prominent in the cytopenic phase from conditioning-related mucosal toxicity; a portal for gram-positive (viridans streptococci) and gram-negative GI-flora bacteremia. Levofloxacin prophylaxis is favored partly to cover mucositis-related S. viridans.
• VOD/SOS (hepatic sinusoidal obstruction syndrome): injury to small hepatic veins/sinusoidal endothelium. Suspect with ascites, painful hepatomegaly, or rising bilirubin within about 3 weeks of transplant; severe SOS causes multiorgan failure. Ultrasound may show reversal of portal flow. DDx: viral/toxic hepatitis, malignancy, ischemia.
• Modified Seattle criteria: two or more of the following within 20 days of HCT: (1) total bilirubin > 2.0 mg/dL; (2) painful hepatomegaly or RUQ pain; (3) sudden weight gain from fluid (> 2% from baseline).
• EBMT criteria (adults): within the first 21 days, bilirubin ≥ 2 mg/dL PLUS two of: painful hepatomegaly, weight gain > 5%, ascites.
• Risk factors: cyclophosphamide, busulfan (PO > IV) conditioning, prior gemtuzumab ozogamicin, prior inotuzumab ozogamicin.
• Treatment: supportive care; defibrotide 6.25 mg/kg IV four times daily (FDA 2016). Pooled analysis of 3 studies: day-100 survival 38% to 45% (defibrotide) vs 21% to 31% (supportive care).
• TA-TMA (transplant-associated thrombotic microangiopathy): consider with unexplained MAHA, thrombocytopenia, and organ dysfunction post-transplant. Narsoplimab (Yartemlea; anti-MASP-2, lectin complement pathway inhibitor) FDA-approved Dec 23, 2025 for TA-TMA in adults and children ≥ 2 years, the first approved therapy; eculizumab (off-label) remains an option for severe disease.

Pulmonary Complications (Non-Infectious)

• Idiopathic pneumonia syndrome (IPS): diffuse alveolar damage with no identified infection; supportive care plus systemic corticosteroids (evidence limited); etanercept is investigational and adding it to steroids has not shown benefit.
• Diffuse alveolar hemorrhage (DAH): occurs in up to 20% after auto or allo HSCT; mortality can exceed 50% if mechanical ventilation is required. Risk: pretransplant high-dose chemo, TBI, thoracic irradiation, older age, renal insufficiency. Mechanism: alveolar capillary endothelial injury and inflammatory cytokine release. Bronchoscopy with BAL confirms intra-alveolar blood (increasingly hemorrhagic sequential aliquots), excludes large-airway source and infection; > 20% hemosiderin-laden macrophages on iron staining supports the diagnosis. Treatment: early high-dose corticosteroids (methylprednisolone 500 mg to 2 g IV daily in divided doses for the first 4 to 5 days, then gradual taper over 2 to 4 weeks), platelet transfusions, and ventilatory support; rFVIIa reported for uncontrolled bleeding refractory to steroids and platelets.

Infection Prophylaxis (Standard Post-Allo)

• Infection risk by phase: pre-engraftment (< 30 days, neutropenia + mucositis): HSV, gram-negative and gram-positive GI-flora bacteria, Candida/Aspergillus. Post-engraftment (30 to 100 days, acute GVHD, impaired cellular immunity): CMV, PJP, Aspergillus. Late (> 100 days, chronic GVHD): Aspergillus, PJP, encapsulated bacteria, VZV.
• Bacterial: fluoroquinolone during myeloablative-conditioning neutropenia; levofloxacin (500 or 750 mg daily) or ciprofloxacin, levofloxacin favored for mucositis-related S. viridans risk; stop at engraftment. base antibacterial prophylaxis on anticipated neutropenia (fluoroquinolone when ANC expected below 100/µL for over 7 days); many RIC/NMA regimens have brief neutropenia and need none, but RIC with prolonged profound neutropenia qualifies. For chronic GVHD, add an agent active against S. pneumoniae for as long as immunosuppression continues (penicillin where resistance is low).
• Fungal: fluconazole 400 mg PO daily (yeast only) from conditioning; for allo-HCT continue through about day +75 (longer, with a mold-active agent, if GVHD or other mold-risk factors). Anti-mold prophylaxis (voriconazole 200 mg BID, or posaconazole) for high-risk patients (eg, AML, prolonged cytopenia, prior pulmonary nodules, high-dose steroids), continued until immunosuppression stops.
• CMV: letermovir prophylaxis for CMV-seropositive recipients in the first 14 weeks (first 100 days) post-transplant (Marty NEJM 2017); extended to 200 days in patients at risk of late CMV (Russo Lancet Haematol 2024; FDA label extension 2023). Letermovir lacks HSV/VZV activity, so acyclovir/valacyclovir is still required. Alternative to prophylaxis is weekly quantitative CMV PCR with pre-emptive IV ganciclovir or oral valganciclovir (foscarnet as alternative), from engraftment to day +100. Refractory/resistant CMV: maribavir (Livtencity), a UL97 inhibitor; FDA Nov 23, 2021 (SOLSTICE, Avery Clin Infect Dis 2022; superior to investigator choice of val/ganciclovir, foscarnet, cidofovir). Less myelosuppression than ganciclovir, less nephrotoxicity than foscarnet. Use CMV-safe (leukoreduced or seronegative-donor) blood products for D-/R- pairs.
• EBV and adenovirus: PCR monitoring in high-risk patients. BK: test for compatible disease (hemorrhagic cystitis), not routine asymptomatic screening. Tabelecleucel (Ebvallo) for EBV+ relapsed/refractory PTLD post-allo (EU approval Dec 2022; NOT FDA-approved: FDA complete response letters Jan 2025 and Jan 2026). BK virus hemorrhagic cystitis: supportive care is the foundation; cidofovir off-label in selected severe cases (limited evidence, nephrotoxic). IVIG not recommended routinely; brincidofovir investigational.
• HSV: acyclovir (400 or 800 mg BID) or valacyclovir (500 mg BID) for HSV-seropositive recipients from conditioning until engraftment/mucositis resolution; longer acyclovir/valacyclovir (mainly for VZV) generally continued for at least 1 year post-transplant, extended while on immunosuppression.
• VZV: VZV-seropositive recipients for at least 1 year; if ongoing immunosuppression (GVHD), continue for 6 months after stopping it.
• PJP: TMP-SMX from engraftment for at least 6 months or until off immunosuppression, whichever is last; also prevents toxoplasmosis.
• Vaccinations: inactivated vaccines can start about 3 to 6 months post-transplant (eg, DTaP, inactivated polio, Hib, hepatitis B, pneumococcal; annual influenza); live attenuated vaccines (eg, MMR) only at about 2 years if ≥ 1 year off immunosuppression and ≥ 8 months since last IVIG.