移植後各項併發症之處置MANAGEMENT OF COMMON COMPLICATIONS AFTER

TRANSPLANT

林建廷 醫師 台灣大學台成幹細胞治療中心 Oct 17, 2009

過五關， 斬六將，活的久，活的好-- 台大醫院移植 25 年

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無病存活率

0 3 6 9 12 15 18 21 年

存活率

0 3 6 9 12 15 18 21 年

( 一 )CONDITIONING AND TOXICITIES 高劑量化療 /電療

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Agent Upper limit dose

Common scheduling

Organ-specific toxicity (<3m)

Organ-specific toxicity (>3m)

TBI 1400-1500 cGy 6-12 fx over 3-4 days

ParotitisSkin erythemaXerostomiaIP

CataractsXerostomiaHypothyroidismGrowth arrestGonadal failureSecond malignancy

Cyclophosphamide

200 mg/kg Over 2-4 days Cardiac failureHemorrhagic cystitis

Cardiac failure

Busulfan (po)

Busulfex (iv)

16 mg/kg

12.8 mg/kg

4 days

QD~Q6H* 4 days

VODHemorrhagic cystitisConvulsionsSkin pigmentation

Alopecia

Etoposide 60 mg/kg Single dose HypotensionHepatotoxicity

Ara-C 36 g/m2 Up to q12h over 6days

Cerebellar toxicity Cerebellar toxicity

Melphalan 200-220 mg/m2 Single dose

Fludarabine 240-250 mg/m2 Over 4-6 days Neurotoxicity

CONDITIONING AND TOXICITIES 高劑量化療 /電療 目的 :

創造空間 抑制免疫功能 ( 避免植入失敗 ) 根治主要疾病

Fatigue Seizure Leukopenia/ Infection Thrombocytopenia/ Bleeding

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ORAL CALORIES INTAKE

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Nausea /vomiting/Loss of appetiteMucositisBowel disturbance/ Diarrhea / Typhilitis

LUNG COMPLICATIONS

IPS: idiopathic pneumonia syndrome CLS: capillary leak syndrome PERDS: engraftment syndrome IP: intersitial pneumonitis DAH: diffuse alveolar hemorrhage RLD: restrictive lung disease OLD: obstructive lung disease

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LUNG COMPLICATIONS

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Pulmonary edema

Engraftment syndrome Fever, lung infiltrate, hypoxemia Treatment: steroid

Idiopathic pneumonia syndrome (IPS) Typically <D+100 Dyspnea 、 hypoxemia 、 fever 、 pneumonitis; but negative BAL exam Incidence ~10% Treatment: supportive, steroid Mortality 60~85%

DIFFUSE ALVEOLAR HEMORRHAGE (DAH)

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Typically <D+30Dyspnea 、 cough 、 hypoxemia 、 hemoptysisCXR: alveolar infiltrate Incidence ~5%Treatment: supportive, steroid

HEART COMPLICATIONS

Cardiac failure Global and profound LV dysfunction~ subtle change Cyclophosphamide

Arrhythmia Bradycardia or tachycardia DMSO

Pericarditis Usually clinical insignificant

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LIVER COMPLICATIONS

Drug/TPN-toxicity Usually transient, self-limited

Viral hepatitis

Iron overload (hemochromatosis)

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VOD (VENO-OCCLUSIVE DISEASE)/ SOS (SINUSOIDAL OBSTRUCTION SYNDROME)

Typically <D+30 Weight gain/ascites, hyperbilirubinemia, painful

hepatomegaly Incidence ~10-60% (decrease gradually)

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DIAGNOSIS OF VOD AND SEVERITY

Mild Moderate Severe

Self-limited Need diuretic, analgesia; finally complete resolution

MOF, esp renal, lung, CNS

D+100 mortality

3% 20% 98%

PAI-1 (plasminogen activator inhibitor) ↑, usually>120 ng/mL PLT ↓ Transvenous liver biopsy Wedged hepatic venous pressure gradient measurement Treatment: supportive + Defibrotide

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POST-TRANSPLANT THROMBOTIC MICROANGIOPATHY (TMA)

So-called HUS/TTP Typically <D+100 Incidence ~5-15% Treatment:

Discontinue calcineurin inhibitor (CsA, Tacrolimus)

Steroid Plasmapheresis: less effective

than classical HUS/TTP Mortality ~75%

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HEMORRHAGIC CYSTITIS

Incidence: 7-70% Severe type in 5% (ranging 0-18%)

Onset: Early onset: cyclophosphamide (mesna rescue) Late onset: BK/JCV, CMV, Adenovirus, aGVHD

Severity: G1: microscopic hematuria > 7 days G2: macroscopic hematuria G3: blood clots G4: impaired renal function

Treatment: Supportive/ transfusion 15

MYELOABLATIVE VS REDUCED-INTENSITY (RIST)

Early toxicity ↓ Early infection ↓ aGVHD, Gr2-4 ↓ aGVHD, Gr3-4 不變 cGVHD 不變

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( 二 )STEM CELLS ENGRAFT OR GRAFT FAILURE幹細胞植入成功或失敗 Engraft definition:

Myeloid ANC >500 /uL *3 days Megakaryocyte PLT >20k/uL *7 days without BT

Incidence of graft failure: (by D+28) Autologous: < 1% Allogeneic, sibling, standard regimen, no T-depletion: 1-2% RIST, or unrelated, mismatched, or T-depleted: higher

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BMT PBSCT CBT

Myeloid (medium days) 14 12 21

Megakaryocyte (medium days) 21 18 28

HLA TYPING (SIBLING AND UNRELATED)

Rate of crossover <2%18

APPROACH FOR GRAFT FAILURE

Review infused stem cells product: CD34 and TNC

Clinical assessment: Drug:

Anti-CMV Ganciclovir, Anti-PJP Baktar

Splenomegaly Virology study:

EBV, CMV, Parvovirus, adenovirus, HHV-6

BM study: Aplasia, hypoplasia Malignancy relapse

Chimerism study: FISH for XX/XY STR

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Chimera: 龍、獅、羊

MANAGEMENT OF GRAFT FAILURE

G-CSF 增加 / 調整免疫抑制劑 Infusion of donor lymphocytes

Loss of donor T-cell chimerism: 有幫忙 Loss of donor myeloid chimerism: 無效

Infusion of donor stem cells without conditioning (booster) For pancytopenia, still donor hemopoiesis

Infusion of donor stem cells with conditioning Original donor New donor

Infusion of other cell products Mesenchymal stem cells (MSC)

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( 三 )INFECTION 感染、斬六將 細菌 黴菌 /PJP 病毒

CMV/EBV HSV/ VZV BK/ JCV

21Day0 Day100

Bacterial

Fungal

HSV CMV/EBV

PJP

1 year (or more)Day30

BK/JC

RECONSTRUCTION OF IMMUNITY 免疫系統重建

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( 四 )GVHD 移植物抗宿主反應

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GVHD 移植物抗宿主反應Risk factors of aGVHD

Generally accepted

HLA mismatchPatient ageDonor ageSex mismatchIntensity of conditioning regimenPBSC> BMSC> CBSCDLI

Controversial

HLA allelesSplenectomyABO incompatibilityCD34 count 24

ACUTE GVHD GRADING

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TREATMENT OF ACUTE GVHD

Primary therapy: Steroid

Steroid-unresponsive: Cyclosporine Tacrolimus (FK-506) Sirolimus ATG Anti-TNF agents Anti-IL2 receptor Ab Anti-CD3 Pentostatin PUVA

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DisabilityQoLEndocrineMetabolismNutritionPain

Ocular sicca

Oral ulcers

Nail dystrophy

Skin sclerosis

Deep sclerosis

Bronchiolitis obliterans

Loss of bile ducts

Fasciitis

Skin ulcers

chronic GVHD

All I m

ages Ar e C

opy righ t Pro t ec t ed

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CHRONIC GVHD

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BO (BRONCHIOLITIS OBLITERANS) VSBOOP (BRONCHIOLITIS OBLITERANS ORGANIZING PNEUMONITIS) Inspiration 吸氣 Expiration

吐氣

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GLOBAL SEVERITY OF CGVHD AND TREATMENT

Category # of organs Maxi score High riska? Systemic Tx

Mild ≦ 2 1 (0 for lung) NY

NYb

Moderate (a) ≧ 3 1 (0 for lung) N/Y Yb

Moderate (b) Any 2 (1 for lung) N/Y Y

Severe Any 3 (2 for lung) N/Y Y

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a, high risk defined as PLT<100k/uL or steroid useb, GVL/ cGVHD should be balanced

TREATMENT OF CHRONIC GVHD

Primary therapy: Steroid + CsA Steroid + Tacrolimus Steroid + Imuran Steroid + CsA + Thado

Steroid-unresponsive: High dose steroid Cyclosporine Tacrolimus (FK-506) MMF Sirolimus PUVA Thado Rituximab Anti-TNF agents

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( 五 )PRIMARY DISEASES 主要疾病Autologous Allogeneic

Immunodeficiency SCID Wiskott-Aldrich dz

*-

++

Autoimmune dz ITP SLE Multiple sclerosis

+++

-++

Bone marrow failure AA/ PRCA - +

Hemoglobinopathy Thalassemia - +

Hema malignancy Myeloid/ Lymphoid + +

Non-hema malignancy Neuroblastoma Germ cell tumor Renal cell carcinoma

+++

(+)(+)+

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PATTERNS OF RESIDUAL DISEASE AND RELAPSE

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CAUSES OF DEATH: CIBMTR (1998-2002)

Diagnosis of persistent or recurrent disease: MRD (minimal residual disease) monitoring Donor-Recipient chimerism monitoring

Lineage-specific chimerism analysis is better

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A.Related B.Unrelated

MANAGEMENT OF DISEASE RELAPSE

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LONG-TERM HCT SURVIVORS 活的久、活得好

Tissue/Organs Late complications Tissue/Organs Late complications

Immune system Infections Oral Sicca syndromeCaries

Endocrine Hypothyroidism (7-15%)HypoadrenalismGonadal failure (<2% pregnant)Growth

Ocular Cataracts (25-40%)Keratoconjunctivitis siccaMicrovascular retinopathy

Liver GVHDViral hepatitisIron overload

Skeletal OsteopeniaAVN (4-10%)

Muscle/ Fascia MyopathyMyositisFasciitis

Vascular Coronary diseaseCVA

Respiratory Intersitial pneumonitisBronchial obliterans (BO) (2-14%)BOOP

QoL DepressionAnxietyFatigueSexuality

Nervous system LeukoencephalopathyCalcineurin neurotoxicityPeripheral neuropathy

Second cancer(2-10%)

Solid tumorsHematologic malignancyPTLD (~1%)

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LONG-TERM HCT SURVIVORS 活的久、活得好

Recommended screening/ prevention 6m 1yr Annually

Dental assessment 1 1 1

Ferritin 1 +

Lung function test 2 +

CXR + + +

Thyroid function test 1 +

Gonadal function assess (postpubertal )♀

1 1

Ocular fundus exam 1 +

Schimer’s test 3 3

Bone density test 1 +

Cardiovascular risk factor assess 1 1

Psychosocial/ QoL assessment 1 1 1

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1.Auto/Allo 2.Allo 3.cGVHD or immunosuppressant

REIMMUNIZATION 疫苗接種死菌 活菌減毒 細菌DPT 3 doses@12m,

14m, 24mVaricella 2 yrs Hib 3 doses@12m,

14m, 24m

HBV 3 doses@12m, 14m, 24m

MMR 2 yrs Pneumococcus polysaccharide

2 dose@12m, 24m

HAV 2 doses

Influenza Annual@6m

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過五關， 斬六將，活的久，活的好

40

無病存活率

0 3 6 9 12 15 18 21 年

存活率

0 3 6 9 12 15 18 21 年