Allogeneic stem cell transplantation

Patient selection

• Recipients should be in good physical condition, and <55 years old.

• Donor and recipient should be fully or closely HLA-matched to reduce the risk of life threatening GvHD or graft rejection.

• Greatest chance of full HLA match is with siblings (small chance of full match with cousins); each sib has ~1:4 chance of full HLA-match.

• Matched-volunteer unrelated donor (MUD) may be sought from donor registries e.g. in UK The National Blood Authority and Anthony Nolan panels.

• Haploidentical sibling may considered as a donor for patients in whom no matched sibling or volunteer donor is available (~40%) and the increased risks of the procedure are acceptable (e.g. poor risk adult AML, Ph-positive adult ALL).

Indications for allogeneic SCT

• Adult AML (poor risk first CR or any second CR)1.

• Adult ALL (poor risk first CR or any second CR)2.

TQC • Severe aplastic anaemia.

290 • Chronic myeloid leukaemia.

• Myelodysplasia.

• Primary immunodeficiency syndromes.

• Thalassaemia major.

• Sickle cell disease.

• Inborn errors of metabolism.

• Relapsed aggressive histology NHL.

• Relapsed Hodgkin's lymphoma.

1. Good risk adult AML should not receive SCT in first remission as outcomes are good for most patients with standard treatment (p156)

2. Most children with ALL will be cured by standard chemotherapy alone—transplantation is reserved for those who relapse. (p475)

Outline of allogeneic SCT procedure

• Patient receives standard conditioning therapy with high dose chemoradiotherapy (e.g. cyclophosphamide (CTX) 120mg/kg + 14Gy fractionated total body irradiation (TBI)) or chemotherapy (e.g. cyclophosphamide 120mg/kg + busulfan 16mg/kg).

• Non-myeloablative conditioning regimens use moderate doses of chemotherapy and immunosuppression to achieve engraftment and have a lower transplant-related mortality and morbidity; utilised to increase age range for allogeneic SCT and permit the use of adoptive immunotherapy with donor lymphocyte infusion (DLI) for residual disease post-transplant.

• In patients receiving MUD or haploidentical SCT, Campath-IH (humanised anti-CD52 monoclonal antibody) is often administered daily for 5d prior to conditioning as an immunosuppressant to 5 the risk of graft rejection.

• For patients with aplastic anaemia less intensive conditioning is used (200mg/kg CTX combined with anti-thymocyte globulin) and because of sensitivity to alkylating agents in Fanconi's anaemia still less intensive conditioning is used.

• One day after completing conditioning treatment, BM or PBSC are harvested from donor and infused IV through a central line.

• In MUD and haploidentical SCT the graft is usually depleted of T lymphocytes prior to infusion to reduce the risk of severe GvHD.

• After 7-21d of severe myelosuppression, haematopoietic engraftment occurs.

• Reverse barrier nursing in a filtered air environment, prophylactic anti-infectives (ciprofloxacin, itraconazole, acyclovir) reduce the risk of infective complications.

• Immunosuppression is required to prevent GvHD and graft rejection; generally methotrexate (in the early engraftment phase) + cyclosporin A (for 6 months).

Mechanism of cure: evidence for graft versus leukaemia (GvL)

effect 297

1. Reduced risk of relapse in patients with acute and chronic GvHD.

2. Increased risk of relapse after syngeneic SCT (no GvHD).

3. Increased risk of relapse after T-lymphocyte-depleted SCT.

4. Delayed clearance of minimal residual disease detected post-SCT.

5. Induction of remission by donor lymphocyte infusion (DLI) after relapse post-SCT.

Early complications of allogeneic SCT

• Overall transplant related mortality for matched sibling allografts is 15-30%, for volunteer unrelated donors may reach 45%.

• Infection: severe myelosuppression together with immune dysfunction from delayed reconstitution or GvHD predisposes to a wide variety of potentially fatal infections with bacterial (Gram +ve and -ve), viral, fungal and atypical organisms. Both HSV and HZV infections are common—may present with fulminant extensive lesions. Main causes of infective death post-transplant are: CMV pneumonitis and invasive fungal infections with moulds e.g. Aspergillus.

• Graft versus host disease (GvHD): Acute GvHD occurs <100d of transplant and chronic >100d. (p324-327)

• Other complications:

- Endocrine infertility (both sexes), early menopause and occasionally hypothyroidism.

- Cataract (TBI induced) >12 months post-transplant.

- EBV associated lymphoma.

- Mild psychological disturbances common (serious psychoses rare).

Follow-up treatment and post-transplant surveillance

Immunosuppression requires careful monitoring to avoid toxicity. Unlike solid organ transplant recipients, lifelong immunosuppression not required and cyclosporin is usually discontinued at about 6 months post-transplant. Prophylaxis against pneumococcal sepsis secondary to hypos-

plenism, HZV reactivation and PCP infections required. Despite these complications, most patients return to an active, working life without the need for continuing medication.

Future developments

Molecular HLA gene loci mapping: improved DNA characterisation of HLA gene loci should permit greater applicability and success of transplants from volunteer unrelated donors.

Umbilical cord blood transplants: umbilical cord blood donation post-delivery shown to be safe for mother and child. Cord blood stem cells are immunologically immature and may be more permissive of HLA donor/recipient mismatches with less risk of GvHD. Successful grafts in children; cell dose insufficient for adult grafts.

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