Hematopoietic CellTransplantation¶
Chapter 119 | Harrison's 22e · Part 4 – Oncology: Hematologic Malignancies · Chapter 119
Key Clinical Points¶
- HLA-matched sibling donors have a 1 − (0.75)^n chance of being compatible.
- Unrelated donor transplants now achieve survival rates comparable to HLA-matched sibling transplants.
- Sinusoidal obstructive syndrome (SOS) is a major complication with peak risk 7–14 days post-transplant.
- Autologous transplants avoid GVHD but risk tumor cell contamination and lack a graft-versus-tumor effect.
- Newer GVHD prophylaxis strategies, such as posttransplant cyclophosphamide, enable transplantation between donor/recipient pairs sharing only one HLA haplotype.
- HLA-identical unrelated donors can be found for ~60% of patients (higher in whites, lower in minorities).
1. DEFINITION & OVERVIEW¶
Hematopoietic cell transplantation (HCT) involves replacing a patient's hematopoietic system with stem cells from a donor or the patient themselves.
• Sources: Bone marrow, peripheral blood, and umbilical cord blood. • Clinical Utility: Treats both malignant and nonmalignant disorders. • Malignancies: Leukemias, lymphomas, multiple myeloma. • Nonmalignant Disorders: Severe aplastic anemia, sickle cell disease, inherited metabolic disorders.
2. STEM CELL CHARACTERISTICS AND MECHANIS_MS¶
Hematopoietic stem cells (HSCs) possess regenerative capacity, homing ability to marrow niches, and cryopreservation viability.
• Homing: Mediated by P/E-selectin interactions with VLA-4 integrins on HSCs. • Migration: Driven by CXCL12-CXCR4 chemokine signaling. • Survival: Characterized by resistance to freezing/thawing damage.
Table 119-1: Stem Cell Source Comparison
| Source | Advantages | Limitations |
|---|---|---|
| Bone marrow | Established method | Invasive harvest |
| Peripheral blood | Higher cell yield | Requires growth factors |
| Umbilical cord blood | HLA-mismatch tolerance | Limited cell numbers |
3. HLA MATCHING AND COMPLICATIONS¶
HLA compatibility determines transplant outcomes:
• Graft-versus-host disease (GVHD): 15% risk in HLA-identical sibling transplants; risk increases with mismatched donors. • Graft Rejection: 1–3% risk with conventional regimens. • Prophylaxis: Newer strategies, such as posttransplant cyclophosphamide (2 g/m² day 3–4), reduce GVHD risks in partially matched pairs.
3.1 HLA Typing Statistics¶
• Odds of HLA identity between unrelated individuals: <1/10,000. • Probability of finding a match: ~60% for whites; lower in minorities. • Registry size: >40 million volunteer donors globally.
Table 119-1: Probability of Identifying a Donor Based on Stem Cell Source and Patient Ethnicity | Ethnicity | Unrelated Adult | Cord | Haploidentical | | --- | --- | --- | --- | | Caucasian | 75% | >95% | 95% | | Hispanic | 35% | 75% | 95% | | Black | 18% | 70% | 90% |
4. TRANSPLANT CATEGORIES¶
HCT is classified by donor relationship and stem cell source:
- Autologous: Patient's own cells (no GVHD risk, but potential tumor contamination).
- Allogeneic: Donor-derived cells (risk of GVHD and graft rejection; provides graft-versus-tumor effect).
- Syngeneic: Identical twin donor (no GVHD, no tumor contamination risk; provides graft-versus-tumor effect).
Table 119-2: Transplant Type Comparison
| Type | GVHD Risk | Tumor Contamination Risk | Graft-Versus-Tumor Effect |
|---|---|---|---|
| Autologous | None | High | None |
| Allogeneic | High | Low | Present |
| Syngeneic | None | Low | Present |
5. COMPLICATIONS AND MANAGEMENT¶
Major complications include:
• Acute GVHD: 15% incidence in HLA-identical transplants; managed with immunosuppression (e.g., tacrolimus, methotrexate). • Infections: • Viral: CMV, HSV, VZV. • Fungal: Candida, Aspergillus. • Bacterial: Gram-positive, Gram-negative, encapsulated bacteria. • SOS (Sinusoidal Obstruction Syndrome): Peak risk 7–14 days post-transplant; managed with defibrotide.
5.1 Prophylactic Strategies¶
- GVHD Prevention: Posttransplant cyclophosphamide (2 g/m² day 3–4).
- Infection Prevention: • Bacterial: Levofloxacin (750 mg PO or IV daily) and Fluconazole. • Pneumocystis jirovecii: Trimethoprim-sulfamethoxazole (1 double-strength tablet PO bid 2 days/week until day 180 or off immunosuppression). • Herpes simplex (HSV): Acyclovir (800 mg PO bid to day 30). • Cytomegalovirus (CMV): Ganciclovir (5 mg/kg IV bid for 7 days, then 5 mg/kg/d 5 days/week to day 100).
- SOS Management: Defibrotide (15 mg/kg every 6 hours).
6. OUTCOMES AND SURVIVAL¶
Survival rates have improved with:
• Better HLA matching: Unrelated donor survival is now comparable to sibling donors. • Enhanced supportive care: Use of TPO agonists for management of thrombocytopenia. • Improved GVHD prophylaxis: Reducing mortality from 30–40% to <10%.
Table 119-3: Clinical Staging and Grading of Acute Graft-Versus-Host Disease
| Clinical Stage | Skin | Liver (Bilirubin, mg/dL) | Gut |
|---|---|---|---|
| 1 | Rash <25% body surface | 34–51 (2–3) | Diarrhea 500–1000 mL/d |
| 2 | Rash 25–50% body surface | 51–103 (3–6) | N/A |
| 3 | Erythroderma / Desquamation & bullae | 103–257 (6–15) | Diarrhea >1500 mL/d |
Table 119-4: Overall Clinical Grade
| Overall Clinical Grade | Skin Stage | Liver Stage | Gut Stage |
|---|---|---|---|
| I | 1–2 | 0 | 0 |
| II | 1–3 | 1 | N/A |
| III | 1–3 | 2–3 | 2–3 |
| IV | 2–4 | 2–4 | N/A |
Table 119-5: Estimated 3-Year Survival Rates Following Transplantation
| Disease | Allogeneic (%) | Autologous (%) |
|---|---|---|
| Severe combined immunodeficiency | 95–98 | N/A |
| Thalassemia | 95 | 53–57 |
| Acute myeloid leukemia (1st remission) | 64 | 71 |
| Acute myeloid leukemia (2nd remission) | 45 | 67 |
| Chronic lymphocytic leukemia | 64 | 50 |
| Multiple myeloma (initial therapy) | N/A | 80 |
| Multiple myeloma (subsequent therapy) | N/A | 45 |
| Hodgkin's disease (1st relapse / 2nd remission) | 68 | 89 |
Reference Tables¶
TABLE 119-1 Probability of Identifying a Donor Based on Stem Cell Source and Patient Ethnicity Ethnicity Caucasian…¶
Harrison's 22e, p.915
| UNRELATED ADULT % | UNRELATED CORD % | HAPLOIDENTICAL | ||
|---|---|---|---|---|
| Ethnicity | 8/8a | 7/8a | ≥4/6b | |
| 75 | 90 | >95 | ||
| Hispanic | 35 | 75 | 95 | 95 |
| 18 | 70 | 90 |
TABLE 119-2 Clinical Staging and Grading of Acute Graft-Versus-Host Disease¶
Harrison's 22e, p.917
| CLINICAL STAGE | SKIN | LIVER—BILIRUBIN, kmol/L (mg/dL) | GUT |
|---|---|---|---|
| 1 | Rash <25% body surface | 34–51 (2–3) | Diarrhea 500–1000 mL/d |
| Rash 25–50% body surface | 51–103 (3–6) | ||
| 3 | Generalized erythroderma | 103–257 (6–15) | Diarrhea >1500 mL/d |
| Desquamation and bullae | >257 (>15) | ||
| OVERALL CLINICAL GRADE | SKIN STAGE | LIVER STAGE | GUT STAGE |
| I | 1–2 | 0 | 0 |
| 1–3 | 1 | ||
| III | 1–3 | 2–3 | 2–3 |
| 2–4 | 2–4 |
TABLE 119-3 Approach to Infection Prophylaxis in Allogeneic Transplant Recipients ORGANISM Bacterial Fungal…¶
Harrison's 22e, p.918
| ORGANISM | AGENT | APPROACH |
|---|---|---|
| Bacterial | Levofloxacin | 750 mg PO or IV daily |
| Fluconazole | ||
| Pneumocystis jirovecii | Trimethoprim- sulfamethoxazole |
1 double-strength tablet PO bid 2 days/week until day 180 or off immunosuppression |
| Herpes simplex | Acyclovir | 800 mg PO bid to day 30 |
| Acyclovir | ||
| Cytomegalovirus | Ganciclovir | 5 mg/kg IV bid for 7 days, then 5 (mg/kg)/d 5 days/week to day 100 |
TABLE 119-4 Estimated 3-Year Survival Rates Following Transplantation a DISEASE Severe combined immunodeficiency…¶
Harrison's 22e, p.919
| DISEASE | ALLOGENEIC, % | AUTOLOGOUS, % |
|---|---|---|
| Severe combined immunodeficiency | 95 | NA |
| 98 | ||
| Thalassemia | 95 | NA |
| 57 53 |
||
| Acute lymphocytic leukemia | ||
| First remission | 64 | ID |
| Second remission | 45 | ID |
| 71 67 28 |
||
| Chronic lymphocytic leukemia | 64 | NA |
| 50 | ||
| Multiple myeloma—initial therapy | NA | 80 |
| 45 | ||
| Hodgkin’s disease | ||
| First relapse/second remission | 68 | 89 |