Hematopoietic stem cell

Hematopoietic stem cell

transplantation

Introduction

IBMTR: 50,000/year, VGHTPE: 75 cases in 2009 Two purpose

• Replace an abnormal but nonmalignant

lymphohematopoietic system with one from a lymphohematopoietic system with one from a normal donor

• Treat malignancy by allowing the administration of higher doses of

myelosuppressive therapy than would otherwise be possible

Why feasible?

• Regenerative capacity

• Homing to the marrow space—bone marrow endothelial cell-surface selectins and integrins

on early hematopoietic cells on early hematopoietic cells

Replace for what

Fixed macrophage Fixed macrophage population, including

Kupffer cells of the liver, pulmonary alveolar macrophages,

osteoclasts, Langerhans cells of

the skin, and brain microglial cells

Source of stem cell-by genetics

• Syngeneic: no GvHD, no contamination, ~1%

• Allogeneic: non immunologically identical donor and recepient, HLA mismatch severity

– GvHD: ~15%

– GvHD: ~15%

– Graft rejection: 1-3%

– Major antigen (exogenous), minor antigen (endogenous)

Source of stem cell-by ggenetics

• Autologous

– no risk of GVHD or graft rejection

– No graft-versus-tumor (GVT) effect, contamination

– "purge" autologous products of tumor cells

Reduce the number of tumor cells from 1000- to 10,000-fold. No prospective randomized trials have

yet shown that any of these

– "purge" autologous products of tumor cells

• Antibodies directed at tumor-associated antigens plus complement

• Antibodies linked to toxins

• Antibodies conjugated to immunomagnetic beads • In vitro incubation with certain chemotherapeutic

agents

• Long-term culture of bone marrow

yet shown that any of these

approaches results in a decrease in relapse rates or improvements in

Source of stem cells-by approach

Bone marrow:

• posterior superior iliac crest, 1.5 to 5 x 108 nucleated marrow cells/kg collected for allogeneic transplantation

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 filtered through 0.3- and 0.2-mm screens to remove fat and bony spicules removal of red cells to prevent hemolysis in

ABO-incompatible 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

Source of stem cell-by approach

collected in one or two 4h pheresis sessions

In the autologous setting, transplantation of >2.5 x 106 CD34 cells/kg recovery, with granulocytes > 500/L by day 12 and platelets > 20,000/L by day 14 ↓ the

morbidity but not survival

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

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

• Slower engraftment and peripheral count

recovery than marrow, engraftment rate ~85%

• Low incidence of GVHD: low number of T cells in cord blood?

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.

Transplantation preparative

regimen

• Eradicate underlying disease

• Immunosuppressing for preventing graft rejection

• SCID need for conditioning?

• SCID need for conditioning?

• SAA need for conditioning?

• busulfan, cyclophosphamide, melphalan, thiotepa, carmustine, etoposide, and TBI in various combinations

Transplantation preparative

regimen

Lowest posttransplant relapse rates in patients with acute

Higher in those without GVHD Higher still in recipients of T cell– depleted allogeneic or syngeneic • Nonmyeloablative

• Donor lymphocyte infusion

GvT

effect

patients with acute and chronic GVHD

or syngeneic marrow

Engraftment

• Influenced by

– The source of stem cells

– The use of posttransplant growth factors

– The form of GVHD prophylaxis employed

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 G-CSF–mobilized PBSC: -7

• Use of a myeloid growth factor (G-CSF or GM-CSF) posttransplant: -3~5

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

– FISH of sex chromosomes if donor and recipient are sex-mismatched

– HLA-typing if HLA-mismatched

Early Direct Chemoradiotoxicities

• Hemorrhagic cystitis/carditis

• Oral mucositis

• Losing their hair

• Pancytopenia

• Pancytopenia

• VOD of liver

Early Direct Chemoradiotoxicities

• High-dose cyclophosphamide: hemorrhagic cystitis acrolein predisposition on bladder wall prevented by bladder irrigation or with the sulfhydryl compound

the sulfhydryl compound

mercaptoethanesulfonate (MESNA); rarely, acute hemorrhagic carditis

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

patient satisfaction and results in a lower cumulative dose of narcotic

• Losing their hair 5–6 days posttransplant

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

with subsequent deposition of fibrin

• Clinical diagnosis: tender hepatomegaly, ascites, jaundice, and fluid retention.

Early Direct Chemoradiotoxicities

• Symptoms: any time during the first month posttransplant, peak incidence at day 16.

• Predisposing factors: prior exposure to intensive chemotherapy, pretransplant 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

Early Direct Chemoradiotoxicities

• Treatment: Both thrombolytic and antithrombotic agents

– Tissue plasminogen activator

– Heparin

– Heparin

– Prostaglandin E,

– but none has proven of consistent major benefit in controlled trials, but with significant toxicity

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 hemorrhage, and biopsies are typically characterized by diffuse alveolar damage

• Treatment: high-dose glucocorticoids (no RCT proved)

Late Direct Chemoradiotoxicities

Late Direct Chemoradiotoxicities

• Decreased growth velocity in children and delayed development of secondary sex

characteristics partly ameliorated by growth and sex hormone replacement growth and sex hormone replacement

• Most men azoospermic; most postpubertal women ovarian failure

• Thyroid dysfunction: usually well compensated

Late Direct Chemoradiotoxicities

• Cataracts: 10–20%, most common in patients treated with TBI and those who receive

glucocorticoid therapy posttransplant for treatment of GVHD

treatment of GVHD

• Aseptic necrosis of the femoral head: 10%, particularly frequent in those receiving

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

antigenic targets on host cells

– Acute GVHD: developing within the first 3 months posttransplant

– Chronic GVHD: developing or persisting beyond 3 months posttransplant

Acute GvHD

• Most often first becomes apparent 2–4 weeks posttransplant

• s/s: erythematous maculopapular rash;

persistent anorexia or diarrhea, or both; and 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.

Acute GvHD

• Pathology: endothelial damage and lymphocytic infiltrates are seen

• In skin, the epidermis and hair follicles are damaged

damaged

• In liver, the small bile ducts show segmental disruption

• In intestines, destruction of the crypts and mucosal ulceration may be noted.

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

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

Prevention of aGvHD

• Immunosuppressive drugs early after transplant

• Most common combinations of MTX and either cyclosporine or tacrolimus

either cyclosporine or tacrolimus

• Others: prednisone, anti–T cell antibodies, mycophenolate mofetil, and other

immunosuppressive agents in various combinations

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

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)

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 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

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

3 years of immunosuppressive treatment before these agents can be withdrawn

without the disease recurring

• Susceptible to significant infection

prophylactic trimethoprim-sulfamethoxazole

Graft failure

• Loss of marrow function sooner or later after transplantation

• After autologous transplantation:

– Inadequate numbers of stem cells being transplanted

– Damage during ex vivo treatment or storage

– Exposure to myelotoxic agents posttransplant. Infections with

– Exposure to myelotoxic agents 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

Graft failure

• Treatment:

– removing all potentially myelotoxic agents from the

patient's regimen

– attempting a short trial of a myeloid growth factor

– Reinfusion of donor stem cells in such patients is

– 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

Infection

• Prophylactic antibiotics: granulocyte count falls to < 500/L

• Fluconazole prophylaxis at a dose of 200–400 mg/kg/day

mg/kg/day

• Acyclovir prophylaxis: seropositive for HSV, may also use for VZV prophylaxis for 1 year

Infection

• Bacterial infection: diminished after patients engraft

• gram-positive bacteria, fungi (particularly

Aspergillus) and viruses including CMV: From

Aspergillus) and viruses including CMV: From engraftment until about 3 months

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 – 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,

Infection

• Pneumocystis jiroveci pneumonia: 5–10% of patients, prevented by oral TMP-SMX for 1 week pretransplant and resuming after

engraftment, suggest indefinitely if engraftment, suggest indefinitely if undergoing immunosuppressant

• 3 months after transplant: ↓ risk of infection, unless chronic GVHD develops, requiring

Treatment of specific

disease~non-malignant

• Any disease that results from an inborn error of the lymphohematopoietic system

• Storage disease which effect hematopoiesis

• Severe acquired autoimmune disorder

• Severe acquired autoimmune disorder

Treatment of specific

disease~non-malignant

• AA: 90% in adults < 40 with sibling donor, in older

patient or no sibling donor, consider

immunosuppresive therapy first, also effective in aplastic anemia like syndrome (Fanconi’s anemia, PNH)

PNH)

• Hemoglobinopathies: best outcomes before

hepatomegaly and portal fibrosis developed in

thalassemia, in sickle cell anemia, repeated crises or other significant complications and who have not responded to other interventions

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

– Cure rates of 30–35% are seen when patients are transplanted in 2nd CR or 1st relapse

– Best results when during 1st CR, with DFS 55–60%

– 1st 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

Malignant disease

Acute lymphoblastic leukemia:

• 15–20% of patients without CR, as in AML

• Cure rates improve to 30–50% in 2nd remission,

recommended for persistent disease after induction recommended for persistent disease after induction chemotherapy or relapse

• Transplantation in 1st remission: cure rates around 55%. Recommended in Philadelphia chromosome– positive disease, debate in standard risk, no

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,

• 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

Malignant disease

Chronic lymphocytic leukemia

• Limited extent due to chronic nature of the disease and age of patients

• With allogeneic transplantation, DFS ~50% at

• With allogeneic transplantation, DFS ~50% at 3 years

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

Malignant disease

Lymphoma

• Cure rate: 40–50% in disseminated

intermediate- or high-grade NHL transplanted in 1st relapse or 2nd remission better than in 1st relapse or 2nd remission better than conventional-dose salvage chemotherapy

• High-risk disease with 1st remission?

• Favor autologous rather than allogeneic (similar survival)

Malignant disease

• Autologous vs salvage therapy in recurrent

disseminated indolent lymphoma: high RR and improved PFS, but late relapses are noted

• Initial autologous transplantation?

• Initial autologous transplantation?

• Nonmyeloablative preparative regimens

followed by allogeneic transplantation: high RR

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 1st remission with standard

chemotherapy and up to 70% for those

transplanted in 2nd remission, no definite role in 1st remission

Malignant disease

Multiple myeloma

• Benefit from autologous/allogeneic HSCT in progressed on first-line therapy

• Autologous transplantation: improve DFS and

• Autologous transplantation: improve DFS and OS

• Tandem transplantation with autologous

transplantation followed by nonmyeloablative allogeneic transplantation maybe

Malignant disease

Solid tumor

• Metastatic breast cancer, 15–20% DFS at 3 years,

• Better results: younger patients who have

• 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.

Malignant disease

• Testicular cancer: failed first-line

chemotherapy have been treated with

autologous transplantation; ~10–20% cure rate

rate

• Ovarian cancer, small cell lung cancer,

neuroblastoma, and pediatric sarcomas, etc: Few randomized trials of transplantation in these diseases have been completed

Relapse after transplantation

• May respond to further chemotherapy,

particularly if the remission following transplantation was long

• DLI: Complete responses in 75% of patients with

• 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,