Hematopoietic stem cell

Transcription

1 Hematopoietic stem cell transplantation

2 Introduction IBMTR: 50,000/year, VGHTPE: 75 cases in 2009 Two purpose Replace an abnormal but nonmalignant lymphohematopoieticsystem with one from a normal donor Treat malignancy by allowing the administration of higher doses of myelosuppressivetherapy than would otherwise be possible

3 Why feasible? Regenerative capacity Homing to the marrow space bone marrow endothelial cell-surface selectins and integrins on early hematopoietic cells Able being cryopreserved

4 Replace for what Fixed macrophage Fixed macrophage population, including Kupffercells of the liver, pulmonary alveolar macrophages, osteoclasts, Langerhanscells of the skin, and brain microglial cells

5 Source of stem cell-by genetics Syngeneic: no GvHD, no contamination, ~1% Allogeneic: non immunologically identical donor and recepient, HLA mismatch severity GvHD: ~15% Graft rejection: 1-3% Major antigen (exogenous), minor antigen (endogenous) 1 (0.75) n, where nequals the number of siblings

6 Source of stem cell-by ggenetics Autologous Reduce the number of tumor cells no risk of from GVHD 1000-to or graft 10,000-fold. rejection No No graft-versus-tumor prospective randomized (GVT) effect, trials have contamination "purge" autologous yet shown that products any of of these tumor cells Antibodies approaches directed results at tumor-associated in a decrease antigens in plus complement relapse rates or improvements in Antibodies disease-free linked to or toxins overall survival. Antibodies conjugated to immunomagnetic beads In vitro incubation with certain chemotherapeutic agents Long-term culture of bone marrow

7 Source of stem cells-by approach Bone marrow: posterior superior iliac crest, 1.5 to 5 x 10 8 nucleated marrow cells/kg collected for allogeneic transplantation

8 10 15 ml/kg of marrow is aspirated, placed in heparinized media filtered through 0.3-and 0.2-mm screens to remove fat and bony spicules removal of red cells to prevent hemolysis in ABOincompatible transplants, the removal of donor T cells to prevent GVHD, or attempts to remove possible contaminating tumor cells in autologous transplantation DMSO, patients more often experience short-lived nausea or vomiting due to the odor and taste of the cryoprotectant

9 Source of stem cell-by approach Peripheral blood: More rapid hematopoietic recovery, with granulocytes > 500/L by day 12 and platelets > 20,000/L by day 14 the morbidity but not survival G-CSF or GM-CSF for 4 or 5 days In the autologous setting, transplantation of >2.5 x 10 6 CD34 cells/kg collected in one or two 4h pheresis sessions

10 Source of stem cell-by approach one log more T cells than are contained in the typical marrow harvest increase risk of GvHD More than balanced by reductions in relapse More than balanced by reductions in relapse rates and nonrelapse mortality, with the use of peripheral blood stem cells resulting in improved overall survival.

11 Source of stem cell-by approach Core blood: 親 屬 間 的 cord blood 若 需 等 新 生 兒 出 生 後 來 刻 移 植, 需 等 待 九 個 月, 並 不 實 用 Slower engraftment and peripheral count recovery than marrow, engraftment rate ~85% Low incidence of GVHD: low number of T cells in cord blood?

12 Source of stem cell-by approach Severe GVHD: 23% Risk of graft failure if the dose of cord blood cells/kg Low cell content of most cord blood Low cell content of most cord blood collections limited the use for adult patients.

13 Transplantation preparative regimen Eradicate underlying disease Immunosuppressing for preventing graft rejection SCID need for conditioning? SAA need for conditioning? busulfan, cyclophosphamide, melphalan, thiotepa, carmustine, etoposide, and TBI in various combinations

14 Transplantation preparative regimen Higher in those without GVHD Lowest posttransplant relapse rates in patients with acute and chronic GVHD Higher still in recipients of T cell depleted allogeneic or syngeneic marrow GvT effect Nonmyeloablative Donor lymphocyte infusion

15 Engraftment Influenced by The source of stem cells The use of posttransplant growth factors The form of GVHD prophylaxis employed

16 Engraftment If marrow is the source of stem cells, recovery to 100 granulocytes/l occurs by day 16 and to 500/L by day 22 Use of G-CSF mobilized PBSC: -7 Use of a myeloid growth factor (G-CSF or GM- CSF) posttransplant: -3~5 Use of MTX to prevent GVHD: +3~5

17 Documentation of Engraftment By clinical, seven days before the day of ANC > 500/μl, or platelet > 20,000/μl In allogeneic transplantation FISH of sex chromosomes if donor and recipient are sex-mismatched HLA-typing if HLA-mismatched RFLP analysis if sex- and HLA-matched

18 Early Direct Chemoradiotoxicities Hemorrhagic cystitis/carditis Oral mucositis Losing their hair Pancytopenia VOD of liver Diffuse interstitial pneumonia

19 Early Direct Chemoradiotoxicities High-dose cyclophosphamide: hemorrhagic cystitis acrolein predisposition on bladder wall prevented by bladder irrigation or with the sulfhydryl compound mercaptoethanesulfonate (MESNA); rarely, acute hemorrhagic carditis

20 Early Direct Chemoradiotoxicities Oral mucositis: typically develops 5 7 days posttransplant and often requires narcotic analgesia PCA pump provides the greatest patient satisfaction and results in a lower cumulative dose of narcotic Losing their hair 5 6 days posttransplant Pancytopenia: 1 week

21 Early Direct Chemoradiotoxicities VOD of liver: ~10%, local hypercoagulable state resulting from direct cytotoxic injury to hepatic-venular and sinusoidal endothelium, with subsequent deposition of fibrin Clinical diagnosis: tender hepatomegaly, ascites, jaundice, and fluid retention.

22 Early Direct Chemoradiotoxicities Symptoms: any time during the first month posttransplant, peak incidence at day 16. Predisposing factors: prior exposure to intensive chemotherapy, pretransplant hepatitis of any cause, and use of more intense conditioning regimens. Mortality: ~30%, with progressive hepatic failure culminating in a terminal hepatorenal syndrome

23 Early Direct Chemoradiotoxicities Treatment: Both thrombolytic and antithrombotic agents Tissue plasminogen activator Heparin Prostaglandin E, but none has proven of consistent major benefit in controlled trials, but with significant toxicity Defibrotide, a polydeoxyribonucleotide

24 Early Direct Chemoradiotoxicities Diffuse interstitial pneumonia: ~5%, result of direct toxicity of the preparative regimen Diagnosis: BAL typically shows alveolar hemorrhage, and biopsies are typically characterized by diffuse alveolar damage Treatment: high-dose glucocorticoids (no RCT proved)

25 Early Direct Chemoradiotoxicities

26 Late Direct Chemoradiotoxicities Growth retardation Infertility Thyroid dysfunction Cataract Aseptic femoral necrosis

27 Late Direct Chemoradiotoxicities Decreased growth velocity in children and delayed development of secondary sex characteristics partlyameliorated by growth and sex hormone replacement Most men azoospermic; most postpubertal women ovarian failure Thyroid dysfunction: usually well compensated

28 Late Direct Chemoradiotoxicities Cataracts: 10 20%, most common in patients treated with TBI and those who receive glucocorticoid therapy posttransplant for treatment of GVHD Aseptic necrosis of the femoral head: 10%, particularly frequent in those receiving chronic glucocorticoid therapy

29 GvHD The result of allogeneic T cells that were either transferred with the donor's stem cell inoculum or develop from it, reacting with antigenic targets on host cells Acute GVHD: developing within the first 3 months posttransplant Chronic GVHD: developing or persisting beyond 3 months posttransplant

30 GvHD

31 Acute GvHD

32 Acute GvHD Most often first becomes apparent 2 4 weeks posttransplant s/s: erythematous maculopapular rash; persistent anorexia or diarrhea, or both; and by liver disease with increased serum levels of bilirubin, ALT/AST, and Alk-P Definite diagnosis: skin, liver, or endoscopic biopsy due to mimicry of many disease.

33 Acute GvHD Pathology: endothelial damage and lymphocytic infiltrates are seen In skin, the epidermis and hair follicles are damaged In liver, the small bile ducts show segmental disruption In intestines, destruction of the crypts and mucosal ulceration may be noted.

34 Acute GvHD Higher in recipients of stem cells from mismatched or unrelated donors, in older patients, and in patients unable to receive full doses of drugs used to prevent the disease Grade I acute GVHD is of little clinical significance, does not affect the likelihood of survival, and does not require treatment

35 Prevention of agvhd Immunosuppressive drugs early after transplant Most common combinations of MTX and either cyclosporine or tacrolimus Others: prednisone, anti T cell antibodies, mycophenolate mofetil, and other immunosuppressive agents in various combinations

36 Prevention of agvhd Removal of T cells from the stem cell inoculum graft failure and of tumor recurrence posttransplant little evidence suggests that T-cell depletion improves cure rates in any specific setting Despite prophylaxis, significant acute GVHD will develop in ~30% (matched siblings) and in as many as 60% (unrelated donors)

37 cgvhd Chronic GvHD: 20-50% of patients surviving >6 months after allogeneic transplantation More common in older patients, in recipients of mismatched or unrelated stem cells, and in those with a preceding episode of acute GVHD s/s: mimicry of autoimmune disorder with malar rash, sicca syndrome, arthritis, obliterative bronchiolitis, and bile duct degeneration and cholestasis

38 cgvhd Treatment: Single-agent prednisone or cyclosporine is standard treatment at present Resolved in most patients, but may require 1 3 years of immunosuppressive treatment before these agents can be withdrawn without the disease recurring Susceptible to significant infection prophylactic trimethoprim-sulfamethoxazole Thourough search of infection pathogen

39 Graft failure Loss of marrow function sooner or later after transplantation After autologoustransplantation: Inadequate numbers of stem cells being transplanted Damage during ex vivo treatment or storage Exposure to myelotoxicagents posttransplant. Infections with cytomegalovirus (CMV) or HHV6 After allogeneic transplantation: Persistence of lymphocytes of host origin in allogeneic transplant recipients immune mediated, most common cause Use of less-immunosuppressive preparative regimens, in recipients of T cell depleted stem cell products, and in patients receiving grafts from HLA-mismatched donors

40 Graft failure Treatment: removing all potentially myelotoxicagents from the patient's regimen attempting a short trial of a myeloid growth factor Reinfusion of donor stem cells in such patients is usually unsuccessful unless preceded by a second immunosuppressive preparative regimen, no suggestion of standard preparative regimen, consider anti-cd3 Abs with high-dose glucocorticoids, fludarabine plus low-dose TBI, or cyclophosphamide plus ATG

41 Infection Prophylactic antibiotics: granulocyte count falls to < 500/L Fluconazole prophylaxis at a dose of mg/kg/day Acyclovir prophylaxis: seropositive for HSV, may also use for VZV prophylaxis for 1 year

42 Infection Bacterial infection: diminished after patients engraft gram-positive bacteria, fungi (particularly Aspergillus) and viruses including CMV: From engraftment until about 3 months posttransplant, most common

43 Infection CMV infection: Prevented in seronegative patients by the use of seronegative blood products, elimination of white blood cells from transfused blood products Ganciclovir, either as prophylaxis beginning at the time of engraftment or initiated when CMV first reactivates as evidenced by development of antigenemia, can significantly reduce the risk of CMV disease in seropositive patients, Foscarnet: ganciclovir resistance or intolerable

44 Infection Pneumocystis jiroveci pneumonia: 5 10% of patients, prevented by oral TMP-SMX for 1 week pretransplant and resuming after engraftment, suggest indefinitely if undergoing immunosuppressant 3 months after transplant: risk of infection, unless chronic GVHD develops, requiring continuous immunosuppression

45 Treatment of specific disease

46 Treatment of specific disease~nonmalignant Any disease that results from an inborn error of the lymphohematopoietic system Storage disease which effect hematopoiesis Severe acquired autoimmune disorder Immunodeficiency

47 Treatment of specific disease~nonmalignant AA: 90% in adults < 40 with sibling donor, in older patient or no sibling donor, consider immunosuppresivetherapy first, also effective in aplasticanemia like syndrome (Fanconi sanemia, PNH) Hemoglobinopathies: best outcomes before hepatomegalyand portal fibrosis developed in thalassemia, in sickle cell anemia, repeated crises or other significant complications and who have not responded to other interventions

48 Malignant disease Acute myeloid leukemia Allogeneic HSCT: cures 15 20% of patients without CR (AML), as well as in ALL Cure rates of 30 35% are seen when patients are transplanted in 2 nd CR or 1 st relapse Best results when during 1 st CR, with DFS 55 60% 1 st CR best if poor cytogenetic since chemotherapy alone can cure a portion of patients Autologous HSCT: also cure a portion of patients with AML with higher recurrence rate

49 Malignant disease Acute lymphoblastic leukemia: 15 20% of patients without CR, as in AML Cure rates improve to 30 50% in 2 nd remission, recommended for persistent disease after induction chemotherapy or relapse Transplantation in 1 st remission: cure rates around 55%. Recommended in Philadelphia chromosome positive disease, debate in standard risk, no autologous suggestion if donor available

50 Malignant disease Chronic myeloid leukemia Allogeneic hematopoietic cell transplantation is the only curative therapy shown currently 5 years DFS 15 20% for patients transplanted for BC, 25 50% for AP patients, and 60 70% for CP patients, with cure rates as high as 80% (allo-sibling), 70% in UR-HSCT Now only reserved for those who fail to achieve a complete cytogenetic response with imatinib, relapse after an initial response, or are intolerant of the drug

51 Malignant disease Chronic lymphocytic leukemia Limited extent due to chronic nature of the disease and age of patients With allogeneic transplantation, DFS ~50% at 3 years Role of RIC transplant?

52 Malignant disease Myelodysplastic syndrome Cure rate: 40-50%, better in younger patients and those with less-advanced disease Recommended only for patients with disease Recommended only for patients with disease categorized as intermediate risk I or greater according to the International Prognostic Scoring System (blasts, karyotype, cytopenias)

53 Malignant disease Lymphoma Cure rate: 40 50% in disseminated intermediate-or high-grade NHL transplanted in 1 st relapse or 2 nd remission better than conventional-dose salvage chemotherapy High-risk disease with 1 st remission? Favor autologous rather than allogeneic (similar survival)

54 Malignant disease Autologous vs salvage therapy in recurrent disseminated indolent lymphoma: high RR and improved PFS, but late relapses are noted Initial autologous transplantation? Nonmyeloablative preparative regimens followed by allogeneic transplantation: high RR

55 Malignant disease Hodgkin's disease: similar approach to intermediate-and high-grade non-hodgkin's lymphoma with transplantation 5 years DFS: 20 30% in patients who never 5 years DFS: 20 30% in patients who never achieve a 1 st remission with standard chemotherapy and up to 70% for those transplanted in 2 nd remission, no definite role in 1 st remission

56 Malignant disease Multiple myeloma Benefit from autologous/allogeneic HSCT in progressed on first-line therapy Autologous transplantation: improve DFS and OS Tandem transplantation with autologous transplantation followed by nonmyeloablative allogeneic transplantation maybe

57 Malignant disease Solid tumor Metastatic breast cancer, 15 20% DFS at 3 years, Better results: younger patients who have responded completely to standard-dose therapy before undergoing transplantation. No role for autologous transplantation has been established in the treatment of breast cancer.

58 Malignant disease Testicular cancer: failed first-line chemotherapy have been treated with autologous transplantation; ~10 20% cure rate Ovarian cancer, small cell lung cancer, neuroblastoma, and pediatric sarcomas, etc: Few randomized trials of transplantation in these diseases have been completed

59 Relapse after transplantation May respond to further chemotherapy, particularly if the remission following transplantation was long DLI: Complete responses in 75% of patients with CML, 40% in MDS, 25% in AML, and 15% in myeloma Complications: transient myelosuppression and GVHD, depend on the number of donor lymphocytes given and the schedule of infusions, with less GVHD seen with lower dose, fractionated schedules