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HEMATOPOIETIC STEM CELL TRANSPLANTATION (HSCT)Transplantation of donor pluripotent cells that can reconstitute all recipient blood lineagesHSCT 5-26Categories of Stem Cell TransplantationFeature Allogeneic (Allo) Autologous (Auto)Donor-recipient relationship Immunologically distinct Donor is also recipientGraft-versus-host disease Yes NoGraft-versus-tumor effect Yes NoRisk of graft contam. w/ tumor No YesRelapse risk (leukemia) Lower HigherTransplant-related mortality Higher Lower• Types of Allo HSCT: based on donor/recipient matching of major HLA antigens onChr. 6 (3 principal genes for serotyping: HLA-A, -B,& -DR; each w/ 2 alleles ∴ 6 major Ag)Matched related (sibling matched at 6/6 major Ag): lowest risk of GVHD; preferred donorMismatched related (eg, 1/6 Ag mismatch) or haploidentical (mismatch at 3/6 Ag):easiest to find, but c risk of GVHD; ∴ need to deplete T cells firstMatched unrelated: c risk of GVHD; ∴ adv. molecular matching of 8 HLA alleles to T riskUmbilical cord blood: HSC processed at birth & stored; T risk of GVHD; tolerate mismatch• Graft-versus-host disease (GVHD): undesirable side effect of allo HSCTallogeneic T cells view host cells as foreign; c incid. w/ mismatch or unrelated donors• Graft-versus-tumor (GVT) effect: desirable consequence of allo HSCT;allogeneic T cells attack host tumor cellsIndications (NEJM 2006;354:1813)• Malignant disease:Auto HSCT allows higher doses of chemo by rescuing hematopoietic system(used for lymphoma, multiple myeloma, testicular cancer)Allo HSCT produces graft-versus-tumor (GVT) effect, in addition tohematopoietic rescue (used for AML, ALL, CML, CLL, MDS, lymphoma)• Nonmalignant disease: allo HSCT replaces abnl lymphohematopoietic system w/ onefrom nl donor (eg, immunodef., aplastic anemia, hemoglobinopathies, ? autoimmune dis.)Transplantation procedure• Preparative regimen: chemotherapy and/or immunosuppression prior to transplantationmyeloablative (traditional): chemotherapy and/or total body irradiation. Goal iseradication of underlying disease for which transplant is being performed.nonmyeloablative (“mini”): reduced-intensity conditioning regimens S Ttoxicity toallow Pts w/ comorbidities or c age to tolerate HSCT. Goal to proceed w/transplant when in disease remission, harnessing GVT effect while tolerating GVHD.• Sources of stem cells:bone marrow (BM): original source of HSCT but now less common than PBSCperipheral blood stem cells (PBSC): easier collection, most commonly used sourceumbilical cord blood (UCB): less stringent HLA-matching requirements, though feweravailable cells from single donor (∴ 2 donors typically combined), slower engraftment• Engraftment: absolute neutrophil count (ANC) recovers to 500/L w/in 2 wk w/ PBSC,3 wk w/ BM, 4 wk w/ UCB. G-CSF accelerates recovery by 3–5 d in all scenarios.Engraftment syndrome: fever, rash, noncardiogenic pulm edema, abnl LFTs, AKI, wt gain.Dx of exclusion, r/o infection, GVHD; Rx w/ IV steroids.Complications• Either direct chemoradiotoxicites associated with preparative regimen or consequencesof interaction between donor and recipient immune systemsTiming and Mechanism of Noninfectious Complications of HSCTTiming 30 d 30–90 d 90 dRegimen- Pancytopenia Growth failurerelated Mucositis, rash, alopecia Hypogonadism/infertilityNausea, vomiting, diarrheaHypothyroidismPeripheral neuropathiesCataractsHemorrhagic cystitisAvascular necrosis of boneVeno-occlusive disease2nd malignancyInterstitial pneumonitisImmune- Acute GVHD Chronic GVHDmediated Primary graft failure Secondary graft failure