Hematopoietic Cell Transplantation basal findings Miroslav Tomíška Internal Medicine, Block 4 5th year students [USEMAP] 2 Terminology of hematopoietic cell transplantation nOriginally Bone Marrow Transplantation, BMT ‒the source of hematopoietic cells was bone marrow ‒BMT has remained the title of scientific journal nHematopoietic cell transplantation, HCT ‒reflects the availability of peripheral blood stem cells ‒HCT covers other sources of stem cells ‒hematopoietic stem cell transplantation, HSCT nAutologous stem cell transplantation ‒autologous peripheral blood stem cell transplantation, auto-PBSCT [USEMAP] 3 History of HCT nResearch to treat radiation sickness in 1950s ‒potential of total body irradiation to treat leukemia nDiscovery of HLA-system 1960s nDiscovery of cyclosporin A 1970s nFirst publication of 100 transplanted patients from Seattle 1977 (Edward Donnall Thomas) nAllogeneic HCT routinly used from 1980s nAutologous PBSCT from 1990s [USEMAP] 4 Main features of autologous and allogeneic HCT Autologous Allogeneic donor and recipient is the same person donor is another person, related or unrelated no immune problem no immunosupression immune difference immunosupresion necessary high-dose chemotherapy is the main effect immune treatment effect graft versus tumor efect, GvT risk of GvHD higher risk of infection frozen graft mostly native graft [USEMAP] 5 Other types of HCT nSyngeneic transplantation (allogeneic) –from identical twin –no GvT, higher risk of relaps nHaploidentical transplantation –family donor, identical in only 1 haplotype –mainly if no other donor is available –requires specific immunosupression nCord blood transplantation –low number of hematopoietic cells for adult transplantation [USEMAP] 6 Collection of hematopoietic cells preparation of the graft nBone marrow collection (from illiac bones) –no stimulation, general anesthesia, 1 night hospital stay –1000 mL of bloody marrow: centrifugation –collection of buffy coat (between red cells and plasma) –return of red cell mass to the donor nPeripheral blood stem cell collection –bone marrow stimulation necessary (several days) •G-CSF (healthy donors for allogeneic HCT) •cytotoxic regimenn + G-CSF (for autologous SCT) –blood cell separation (extracorporal centrifugation) –buffy coat removal (CD34+ cells), plasma and RC return [USEMAP] 7 Different types of allogeneic HCT Various combinations for transplant treatment related family donor typically sibling unrelated donor from a register HLA identical donor 5/5 identity HLA non-identical donor 1 or 2 missmatches myeloablative conditioning non-myeloblative needs more immunosupression peripheral blood stem cells bone marrow cells [USEMAP] 8 Total Body Irradiation, TBI as part of conditioning prior HCT nEffects of TBI in conditioning prior to alloHCT –cytotoxic effect (anticancer tratment effect) –imunosupression –spacing effect in bone marrow nDoses of TBI in HCT –myeloablative dose 12-15 Gy, 8-12 fractions, 4 days –low-dose TBI 2-8 Gy, 1-4 fractions nRegimens currently used in this dept –myeloablative 10 Gy (5 fractions by 2 Gy) –non-myeloablative 4 Gy or only 2 Gy nConditioning need not contain TBI § [USEMAP] 9 Immunosupression in alloHCT starts as prophylaxis since conditioning nAnti-thymocyte globulin, ATG –rabbit globulin, halflife 20 days –inhibition of human T-lymfocytes –i.v. infusion, risk of reaction - requires prophylaxis –part of conditioning nCyclosporin A (CsA) i.v. or capsules –calcineurin inhibitor, inhibits T-lymphocyte activation –starts prior to transfusion of the graft –continues for several months nCsA is usually combined (2-drug regimen) –methotrexate (MTX) Day +1, +3, +6, +11 –mycophenolate mofetil [USEMAP] 10 Immune effect of the graft is mediated by cytotoxic T-lymfocytes against healthy tissues GvHD against tumor/leukemia GvL T lymfocytes within the graft cytotoxic T-cells Skin and mucosa exanthema watery diarrhea anorexia jaundice, GGT benefitial DLI, donor lymphocyte infusion methylprednisolone 2 mg/Kg/day Cyclosporine A Cyclosporine A [USEMAP] 11 Arrangement of allogeneic HCT model situation Conditio ning 6-12 days Graft transfusion Day 0 BM depression Neutropenia 14-20 days Engraft ment Dis charge -12 -1 0 +1 +14 +21 +25 +30 Combined immunosupression (6 months) [USEMAP] 12 Main reasons for allogeneic HCT nAcute leukemia (AML, ALL) ‒after prior induction and consolidation chemotherapy nMyelodysplastic syndrome ‒sometimes as first-line treatment nChronic lymphoproliferation ‒malignant lymphoma, CLL ‒mostly after failure of prior treatment nCML ‒after failure of targeted therapy with TKIs nAplastic anemia (nonmalignant disease) [USEMAP] 13 Non-myeloablative regimens, NMR characteristics and advantages nLower total dose of cytotoxic drugs/TBI ‒lower side effects, lower toxicity ‒myeloablative regimens are suitable up to 40 yr nNMRs are good options for –patients > 40 yr, up to 65 yr •decreased organ function reserves compared to young pts. –comorbidity (chronic disease) [USEMAP] 14 Specific complications after allo HCT may be lifethreatening and may cause death nMucositis (mucosal toxicity of conditioning) ‒oropharyngeal ‒gastrointestial (both can be severe) nVeno-Occlusive Disease, VOD ‒Sinusiodal Obstructive Syndrome, SOS nInfections owing to prolonged neutropenia and immunosuoression ‒bacterial, including sepsis ‒deep fungal (tissue) infection (invasive) ‒viral nAcute Graft versus Host Disease, GvHD n [USEMAP] 15 Principals of autologous PBSCT nHigh-dose chemotherapy (HD chemo) –brings all treatment effect –qualitatively higher as compared to conventional dose –overcomes heterogeneity od tumor tissue •areas/cells with lower chemosensitivity –high dose of cytotoxic agents kill much more cancer cells –alkylating agents are suitable for HD treatment nTransfusion of stem cells (graft) is supportive –enables to overcome myelotoxicity of HD chemo –auto PBSCT is only suitable for chemosensitive tumors [USEMAP] 16 Arrangement of autologous HCT model situation Conditio ning 1-6 days Graft transfusion Day 0 Neutropenic period 10-15 days Engraft ment Dis charge -6 -1 0 +1 +10 +14 +15 G-CSF [USEMAP] 17 Main reasons for autologous PBSCT transplantation is not the option for advanced disease nMalignant lymphoma –only after failure of 1st line treatment –requires to use salvage regimen prior to autoPBSCT –reduction of tumor burden confirms chemosensitivity nMultiple myeloma –used routinely after several cycles of 1st line treatment –up to 70 yr in good biological age –High Dose (HD) melphalan for conditioning –prolongs life, but is not curative nExceptionally acute leukemia –if unsuitable for allo HCT [USEMAP] 18 Antimicrobial therapy in HCT nProphylaxis in HCT ‒pneumocystis jiroveci (carinii): co-trimoxazole ‒herpes viral infections: aciclovir ‒fungal infections: fluconazole or posaconazole nPreemptive treatment ‒PCR confirmation of CMV reactivation •positive laboratory tests with no clinical signs nEmpirical treatment due to clinical sings ‒antibacterial: from diagnosis of FN / sepsis ‒antifungal: Day 5-7 in persistent fever/signs nTreatment of proved infection [USEMAP] 19 Invasive Fungal Infections, IFIs Invasive Fungal Disease IFD nPossible IFD ‒host factors and clinical signs (without mycological evidence) nProbable IFD ‒host factors identifying the patient at risk ‒clinical signs/symptoms consistent with IFD •halo sign/air-crescent sign/cavity on pulmonary HRCT scan ‒mycological evidence •culture or microscopic analysis •indirect tests: antigen detection (galactomannan, glucan) nProven IFD ‒histological analysis ‒culture of a tissue specimen from the site of disease [USEMAP] 20 Oropharyngeal mucositis in HCT presentation and treatment nPain management ‒opioids, continuously ‒NSAIDs, short infusions (prior to meals), around the clock nRinses of the mouth ‒benzydamin (locally acting NSAID) ‒antiseptics (chlorhexidine, povidon iodine) ‒calcium phosphate precipitating formulation nNutritional support ‒ONS for sipping ‒parenteral nutrition Symptoms/signs: mouth pain, stomatitis, mucosal ulceration, dysphagia, salivation, acumulation of mucus, aspiration [USEMAP] 21 Gastrointestinal mucositis in HCT presentation and treatment nTreatment of diarrhea ‒loperamide, diphenoxylate ‒octreotide (somatostatin analgue) ‒fidaxomycin in Clostridium difficile infection nPain management ‒peripheral analgetics, spasmolytics ‒opioids nNutritional support ‒total parenteral nutrition n n Symptoms/signs: diarrhea, flatulence, abdominal pain, crampi, nausea, vomiting [USEMAP] 22 The End [USEMAP]