30 Basics of Transplantation
- Classification: Autologous (patient’s own HSC) vs allogeneic (donor HSC)
- Autologous efficacy from high-dose chemotherapy; allogeneic from GVM & GVHD
- Indications & fitness vary by center; assess disease burden, HCT-CI, immunosuppression capacity
- HCT process: Assessment → donor/collection → conditioning → infusion/engraftment → long-term care w/ GVHD management
- Infection risk spans entire timeline; ↑ risk w/ GVHD & immunosuppression
- Early referral critical: 4-6 weeks for evaluation & donor screening
30.1 HCT Basics
Definition & Types: - Hematopoietic stem cell transplantation (HCT): Curative/disease-control tx for hematologic malignancies & nonmalignant diseases - Stem cell sources: - Autologous: Patient’s own HSC - Allogeneic: Donor HSC (matched sib, MUD, haploidentical, cord blood) - Efficacy mechanisms: - Autologous: High-dose chemotherapy toxicity - Allogeneic: Graft-versus-malignancy (GVM) & GVHD
HCT process: 1. Disease & fitness assessment 2. Donor selection & stem cell mobilization 3. Conditioning therapy 4. Stem cell infusion & engraftment 5. Long-term care w/ GVHD prophylaxis/management
30.2 Eligibility, Mobilization, & Donor Evaluation
30.2.1 Disease & Fitness Assessment
Transplant eligibility factors: - Disease burden & risk stratification - HCT-Comorbidity Index (HCT-CI): Predicts 3-year overall mortality - Patient capacity to tolerate immunosuppression - Functional status (performance status, psychosocial support) - Age: May inform decision but not absolute contraindication - Elderly w/ good performance status show comparable/better survival
30.2.2 Stem Cell Mobilization & Cell Dose
Autologous HSC collection: - G-CSF ± CXCR4 inhibitor mobilization of HPCs - Collection goal: ≥2 × 10^6 CD34+ cells/kg - Optimal CD34+ dose: 1–10 × 10^6/kg (↑ survival & rapid engraftment) - Factors ↑ cell yield: - High-dose chemotherapy w/ G-CSF - CXCR4 antagonists (plerixafor)
Allogeneic HSC dose: - Optimal CD34+ dose: 1–10 × 10^6/kg (↑ survival, faster engraftment) - Doses >10 × 10^6/kg: No ↑ benefit; ↑ aGVHD & graft failure - Graft source comparison: - Peripheral blood: ↓ graft failure (3% vs 9% BM, BMT CTN 201) - Bone marrow: Traditional gold standard, ↓ relapse
30.2.3 Donor Selection (Allogeneic)
HLA matching hierarchy: - 8/8 match: HLA-A, B, C, DRB1 (4 alleles = 8) → optimal outcomes - 10/10 match: + HLA-DQB1 (improved for some indications) - Mismatched unrelated donors: ↓ survival vs matched - Donor types: - Matched related (MRD) - Matched unrelated (MUD) - Haploidentical (½ match): Feasible w/ PTCy - Cord blood: HLA-A, B, C, DRB1, DQB1, DPA1, DPB1 typing
Additional donor factors: - Age: Younger → better outcomes - Sex: Female donor (age >22y) → ↑ graft failure & cGVHD - CMV serostatus: CMV+ donor w/ CMV− recipient → ↑ infection risk - ABO incompatibility: - Major: ↑ graft failure & hemolytic transfusion reactions - Minor: ↑ transfusion requirements & hemolysis - Donor-specific antibodies (DSA): ↑ transplant failure risk
30.3 Conditioning, Stem Cell Infusion, & Engraftment
30.3.1 Conditioning Regimens
By intensity: - Myeloablative (MAC): Eradicate residual disease, prevent rejection, sustained engraftment - Examples: Bu/Cy, TBI-based regimens - Reduced-intensity (RIC): Preserve some immune tolerance, myelosuppressive - Examples: Flu/Mel, Flu/Bu - Nonmyeloablative: Minimal myelosuppression; rely on GVL/GVM
Regimen composition: - Base drugs: Alkylating agents (busulfan, melphalan, cyclophosphamide) - Modality: - TBI-based: Whole-body irradiation - Chemotherapy-based: e.g., Bu/Cy, Flu/Bu, Flu/Mel - Combination: Multi-agent approaches
Table 30-1: HCT Conditioning by Disease Indication {.striped}
| Disease Indication | Setting | Conditioning Regimen | Notes |
|---|---|---|---|
| Acute leukemia | Newly diagnosed | TBI/Cy or Flu/Bu | |
| Relapsed/refractory | Flu/Bu or TBI/Cy | High-dose Ara-C ↓ relapse | |
| CML | Newly diagnosed | TBI/Cy | |
| Accelerated/blast | TBI/Cy + ifosfamide; Bu ± Cy | Thiotepa: skin toxicity; Bu: daily showers × 48h | |
| Lymphoma | Relapsed/refractory | BEAM (BCNU/VP16/Ara-C/Mel) | |
| Severe aplastic anemia | Relapsed/refractory | TBI/Cy + eATG | |
| Systemic sclerosis | Relapsed/refractory | Cy + TBI ± aATG ± anti-CD52 |
30.3.2 Stem Cell Infusion & GVHD Prophylaxis
GVHD prophylaxis platforms: - Initiated pre-infusion (day 0 = stem cell infusion) - Mechanism: Inhibit donor T-cell alloimmunization vs host tissue - PTCy-based regimens (increasingly standard): - PTCy (post-transplantation cyclophosphamide): High-dose on days 3, 5 post-infusion - Combined w/: Anti-thymocyte globulin, tacrolimus, methotrexate - Benefit: ↓ aGVHD & cGVHD vs calcineurin inhibitor alone - Enables haploidentical & mismatched grafts
Graft failure prevention: - ↑ HPC number: Reduces primary graft failure risk - ↑ Conditioning intensity: Improves engraftment - Monitor: ANC trends post-infusion
30.3.3 Engraftment Definition
Engraftment milestones: - ANC engraftment: ANC ≥500/μL × 3 consecutive days (typically day 14–21 allogeneic) - Platelet engraftment: Plt ≥20,000/μL without transfusion - Autologous: Faster engraftment vs allogeneic (better stem cell yield)
Graft failure definitions: - Primary graft failure: ANC <500/μL by day 21 post-infusion - Secondary graft failure: Initial ANC recovery then ↓ (w/ or w/o alloimmunization) - Autologous: Graft failure rare w/ adequate CD34+ collection
30.4 Posttransplant Recovery & Immune Reconstitution
Post-HCT timeline & complications:
Table 30-2: HCT Complications by Transplant Phase {.striped}
| Complication | Phase I: Conditioning | Phase II: Cytopenia | Phase III: Early Engraftment | Phase IV: Early Convalescence | Phase V: Late Convalescence |
|---|---|---|---|---|---|
| Timing | D−10 to D0 | D0–engraftment | Engraftment +7d | D+31 to 6–12mo | >12 months |
| Infections | Catheter | GPC/GNR (mucosa), HSV, fungi, catheter | Resistant GPC/GNR, fungi, CMV, EBV, other viruses | Viral reactivation, PCP, encapsulated GPC, EBV-PTLD | Viral (if aGVHD), encapsulated GPC |
| GI | Nausea, vomiting, diarrhea | Mucositis, diarrhea, nausea | Protracted nausea; sx of upper GI aGVHD | Gut aGVHD: diarrhea, pain, nausea | |
| Hepatic | Transaminitis | Transaminitis, SOS | Transaminitis, SOS, liver aGVHD | Viral, liver aGVHD/cGVHD | Cirrhosis |
| Cardiac | Arrhythmias (rare), fluid overload | Arrhythmias | HTN (CNI) | HTN (CNI) | CHF, premature CAD |
| Pulmonary | Pneumonitis (rare) | Infectious pneumonia, IPS, fluid overload | Infectious pneumonia, IPS, diffuse alveolar hemorrhage | COP, infectious pneumonia | BOS, hyperactive airway, infection |
| Neurologic | Seizures (busulfan; w/ prophylaxis rare) | PRES (CNI) | PRES (CNI) | PRES (CNI) | Cognitive dysfunction, memory loss |
| Endocrine | Hyperglycemia | Hyperglycemia (CNI) | Hyperglycemia, hypomagnesemia | Hyperglycemia, hypomagnesemia | Metabolic syndrome |
| Renal | ↑ Cr, electrolyte abnormalities | ↑ Cr (drugs), electrolyte disturbances | ↑ Cr, electrolyte disturbances | Chronic kidney disease | CKD |
| aGVHD | Initial: rash, fevers | Late aGVHD: acute diarrhea, rash, ↑ transaminitis, hyperbilirubinemia | |||
| cGVHD | Usually w/ IS withdrawal | Dry eyes/mouth, oral ulcers, sclerotic skin, alopecia, joint stiffness | |||
| Other | TA-TMA (CNI/sirolimus) | PTLD, TA-TMA | Cataracts, 2° malignancies |
: Abbreviations: aGVHD, acute GVHD; BOS, bronchiolitis obliterans syndrome; CAD, coronary artery disease; CHF, congestive heart failure; CMV, cytomegalovirus; CNI, calcineurin inhibitor; COP, cryptogenic organizing pneumonia; CKD, chronic kidney disease; Cr, creatinine; D, day; eATG, equine ATG; EBV, Epstein-Barr virus; GPC, gram-positive cocci; GNR, gram-negative rods; HTN, hypertension; IPS, idiopathic pneumonia syndrome; IS, immunosuppression; PCP, Pneumocystis jirovecii pneumonia; PRES, posterior reversible encephalopathy syndrome; PTLD, posttransplant lymphoproliferative disorder; SOS, sinusoidal obstruction syndrome; TA-TMA, transplant-associated thrombotic microangiopathy
30.5 HCT Complications
30.5.1 Myelosuppression
Universal post-conditioning: - Stems from high-dose chemotherapy (Cy, Bu, TBI, Ara-C) & wide-spectrum antibiotics - Expected nadir: Days 7–14 post-conditioning - Requires broad supportive care (GCSF, transfusions, antimicrobials)
30.5.2 Graft Failure
Primary graft failure: - ANC <500/μL by day 21; plateau or decline post-infusion - Risk factors: Inadequate CD34+ dose, ↓ conditioning intensity, HLA mismatch - Management: Consider 2nd transplant, growth factors
Secondary graft failure: - Initial ANC recovery then sustained ↓ post-engraftment - Causes: Infections (CMV, fungal), alloimmunization, immune rejection - Associated w/ chronic GVHD
30.5.3 GVHD
aGVHD (acute GVHD): Day 0–100
- Targets: Skin, GI, liver
- Skin: Erythematous rash (grade 1–4 severity); pruritus common
- GI: Diarrhea ± crampy pain; nausea/vomiting (upper GI involvement); anorexia
- Liver: Often asymptomatic; ↑ bilirubin, transaminitis on labs
- Diagnosis: Clinical + tissue biopsy (apoptotic bodies)
- Grading: Based on extent of organ involvement (grades I–IV)
cGVHD (chronic GVHD): Day >100
- Targets: Skin, eyes, mouth, GI, lungs, liver
- Manifestations: Sclerotic skin, dry eyes/mouth, oral ulcers, alopecia, fasciitis, joint stiffness
- Risk factors: Prior aGVHD (strongest), older recipient/donor age, female donor
- Morbidity: Can be severely disabling; impacts quality of life long-term
GVHD management: - Mild/localized: Topical therapies (skin creams, oral rinses) - Moderate-to-severe: Systemic corticosteroids (1st-line) - Refractory: Calcineurin inhibitors, other agents (CNI details in separate section)
30.6 Survivorship & Long-Term Follow-Up
Annual post-HCT monitoring: - Screening: Endocrinopathies (hypothyroidism, iron overload), cardiac, pulmonary, renal function - Cancer surveillance: Secondary malignancies (2° solid tumors); cumulative incidence ~2.2% (10y), ~6.7% (15y) - Infectious prophylaxis/monitoring: Especially if ongoing GVHD/immunosuppression - GVHD management: Assessment & treatment if present - Mental health & rehabilitation: Post-traumatic stress, cognitive dysfunction, musculoskeletal complications
Success factors: - Early referral (4–6 weeks for evaluation & donor search) - Careful donor/conditioning selection - Attentive monitoring each transplant phase - Timely intervention for complications - Long-term survivorship care
Clinical Pearls: - Early referral essential: Allows sufficient time for evaluation, HLA typing, & donor identification before transplant urgency - Infection management: Prophylactic/empiric antibiotics during neutropenic phase; infection risk persists long-term, especially w/ GVHD - Survivorship focus: Secondary malignancy, relapse, & GVHD remain concerns; annual screening reduces late mortality