Where in the TED Does HCT Stuff Go?

Transcription

1 Where in the TED Does HCT Stuff Go? Diane J. Knutson TED07_1.ppt Key Concepts What is an HSCT? Why perform one? Who can benefit? Mechanics of transplant Early and Late complications Where on new TED? TED07_2.ppt Introducing Pre-TED & Post-TED TED07_3.ppt 1

2 Blood is Made in the Bone Marrow Axial skeleton Inner spongy bone Bone marrow is in the holes Bone marrow is a highly organized/ regulated organ TED07_4.ppt Bone Marrow: The Source of Blood and Our Immune System Normal bone marrow Blood stem cells Pluripotent Self renewing Highly regulated production Cytokines (SCF, IL3) Growth factors (G-CSF) TED07_5.ppt Hematopoiesis Scheme Stem Cell Compartment Lymphoid Compartment Myeloid Compartment TED07_6.ppt 2

3 Goals of HSCT Provide stem cell replacement Autologous and allogeneic Destroy malignancy Potentially lethal chemotherapy/radiation Immunotherapy TED07_7.ppt Indications for Allogeneic Hematopoietic Stem Cell Transplants, 2003 Worldwide 4,500 4,000 Related donor (Total N=8,800) Unrelated donor (Total N=4,900) Transplants 3,500 3,000 2,500 2,000 1,500 1, AML ALL CML Lymphoma MDS/MPS Other Other Aplastic Other Non- Leukemia Cancer Anemia malignant Disease Slide 7 TED07_8.ppt Pre-TED AML TED07_9.ppt 3

4 100-day Mortality after HLA-identical Sibling Myeloablative Transplants, Mortality, % st Complete Remission 2 nd Complete Remission Not in Remission Chronic Phase Accelerated Phase Blast Phase 20 0 AML ALL CML MDS Aplastic Immune Anemia Deficiency Slide 12 TED07_10.ppt Acute Leukemia section TED07_11.ppt Hematopoietic Stem Cell Transplantation Allogeneic HLA-identical Other Unrelated sibling relative Autologous Donor Bone Peripheral Umbilical marrow Blood cord blood Bone marrow Peripheral blood Collection Negative Positive Ex vivo selection selection expansion Negative Positive Ex vivo selection selection expansion Manipulation TED07_12.ppt 4

5 Basics of HLA HLA = human leukocyte antigens Proteins on cell surfaces that are key players in immune response TED07_13.ppt HLA Class 1 = HLA- A, B, C Class 2 = HLA- DR, DP, DQ Differ in types of organisms they recognize and cells on which they are found TED07_14.ppt HLA Compatible Donor Varies among HSCT centers Varies among protocols Current acceptable donor A, B serologic match? DRB1 allele match TED07_15.ppt 5

6 Antigen vs Allele Antigen = protein on surface of cells (serology) Allele = gene (DNA) TED07_16.ppt What is a Match? P: A1, A2, DR1 B7, B8, DR3 A*0101, A*0201, DRB1*0101 B*0702, B*0801, DRB1*0301 D: A1, A3, DR1 B7, B8, DR3 A*0101, A*0301, DRB1*0101 B*0702, B*0803, DRB1*0304 Serology DNA-Based TED07_17.ppt Pre-TED Donor Type TED07_18.ppt 6

7 Hematopoietic Stem Cell Transplantation Allogeneic HLA-identical Other Unrelated sibling relative Autologous Donor Bone Peripheral Umbilical marrow Blood cord blood Bone marrow Peripheral blood Collection Negative Positive Ex vivo selection selection expansion Negative Positive Ex vivo selection selection expansion Manipulation TED07_19.ppt Complications: Timeline of HSCT Acute and/or chronic GvHD Viral infections CMV, VZV, PCP, IP Bacterial infections HSV mucositis VOD Secondary tumors, cataracts, endocrine changes, QoL Blood & Marrow Changes: PBSC/BM harvests in ABMT Collect & freeze gcsf eg: DHAP and GF and PBSC BM/SC re-infusion Marrow function Immune function BMT Process: Donor search or obtain autologous stem cells Chemo XRT Red cell transfusions Platelet transfusions Growth factors Supportive Antiemetics Therapy: Nutrition Antibiotics TIME LINE months Disease State: Primary diagnosis and treatment Relapse and salvage therapy High-dose myeloablative therapy Marrow failure Disease remission Disease recurrence Continuous complete remission (cure) TED07_20.ppt Allogeneic Stem Cell Sources by Recipient Age Transplants, % Bone Marrow (BM) Peripheral Blood (PB) Cord Blood (CB) Age 20 yrs Age >20 yrs Slide 2 TED07_21.ppt 7

8 Cord Blood Transplants, Registered with the CIBMTR, Related Unrelated 400 Transplants * 2004 * * Data incomplete Slide 11 TED07_22.ppt Cell Source section TED07_23.ppt Hematopoietic Stem Cell Transplantation Allogeneic HLA-identical Other Unrelated sibling relative Autologous Donor Bone Peripheral Umbilical marrow Blood cord blood Bone marrow Peripheral blood Collection Negative Positive Ex vivo selection selection expansion Negative Positive Ex vivo selection selection expansion Manipulation TED07_24.ppt 8

9 Pre-TED Graft Manipulation TED07_25.ppt Most Commonly Used Preparative Regimen Agents HLA-ident Unrelated Autosib BMT- Donor BMT- HSCT malignancy malignancy Lymphoma TBI 52% 85% 25% Cytoxan 87% 91% 85% Busulfan 48% 17% 10% Etoposide 24% 19% 73% Ara-C 5% 10% 25% Thiotepa 4% 14% 8% Platinum* <1% <1% 7% Nitrosourea** 1% <1% 53% * cis-platinum / carboplatin ** BCNU / CCNU TED07_26.ppt A Continuum of Non-myeloablative myeloablative/reduced Intensity Prep Regimens Immunosuppression Genetic Disparity Haplo / T-cell Dep MUD Matched sibling F+TBI 2Gy F+Cy TBI 2Gy Cy + ATG + Thymic XRT Flag-Ida FM Bu8+F+ATG BEAM TBI+Cy TBI+F+TT Bu16+Cy Myelosuppression CLL / CML LCL AML LGL MM Aggressiveness Of Malignancy TED07_27.ppt 9

10 Allogeneic Transplants, Registered with the CIBMTR, ,000 9,000 Reduced Intensity Conditioning Traditional 8,000 Transplants 7,000 6,000 5,000 4,000 3,000 2,000 1, * * Data incomplete Slide 16 TED07_28.ppt Pre-TED Preparative Regimen TED07_28.ppt Trends in Autologous Transplants Recipient Age* Transplants, % yrs yrs yrs yrs >60 yrs * Transplants for AML, ALL, NHL, Hodgkin disease, Multiple Myeloma Slide 5 TED07_30.ppt 10

11 Pre-TED Co-morbid Conditions TED07_31.ppt Pre-TED Therapy Planned as of Day 0 TED07_32.ppt Post-TED TED07_33.ppt 11

12 Enhance/Monitor Recovery Administer growth factors G-CSF, GM-CSF Monitor hematopoietic recovery Cell number and type (granulocytes, platelets, etc.) Marrow cellularity Chimerism (X/Y, VNTR, HLA) TED07_34.ppt ANC recovery (not engraftment) Report first of three consecutive days of ANC greater than 500 Usually not before 8-10 days for myeloablative HSCT May never become neutropenic for reducedintensity TED07_35.ppt Post-TED ANC Recovery TED07_36.ppt 12

13 Complications Graft rejection Graft vs host disease Relapse of disease Infection Regimen-related toxicity TED07_37.ppt Graft vs Host Disease/Graft Rejection HLA differences stimulate detrimental immune responses GvHD Rejection Stem Cells TED07_38.ppt Factors Influencing Risk Of GVHD Donor/Graft-related HLA-disparity Female Male Parity Older age T-cell dose AGVHD (for CGVHD) Recipient-related Older age Prior viral infection/exposure Other microbial infection Treatment-related Conditioning regimen Inadequate immune suppression TED07_39.ppt 13

14 Acute GVHD Glucksberg Staging (organs) Criteria Stage Skin Liver Intestinal tract* (Bilirubin) (Diarrhea) None or Stage 0 No rash <2.0 mg/dl or <500 ml/day or <35 mmol/l <280 ml/m 2 /day Maculopapular >500 but Stage 1 rash, <25% mg/dl or <1000 ml/day or of body surface mmol/l ml/m 2 /day Maculopapular >1000 but Stage 2 rash, 25-50% mg/dl or <1500 ml/day or of body surface mmol/l ml/m 2 /day Stage 3 Generalized mg/dl or >1500 ml/day or erythroderma mmol/l >833 ml/m 2 /day Generalized Severe abdominal Stage 4 erythroderma >15.0 mg/dl or pain, with or with bullae >356 mmol/l without ileus formation and desquamation *use ml/day for adult patients and ml/m 2 /day for pediatric patients TED07_40.ppt Overall Grade Grade I Stage 1 to 2 skin rash; no gut involvement; no liver involvement; no decrease in clinical performance Grade II Stage 1 to 3 skin rash; Stage 1 gut involvement or liver involvement (or both); mild decrease in clinical performance Grade III Stage 2 to 3 rash; Stage 2 to 3 gut involvement or Stage 2 to 4 liver involvement (or both); marked decrease in clinical performance Grade IV Similar to Grade II with Stage 2 to 4 organ involvement and extreme decrease in clinical performance Thomas ED - N Engl J Med Apr 24; 292(17): TED07_41.ppt Chronic GVHD Poorly understood late manifestation Both alloimmune and autoimmune features In part a failure of thymus function Incidence ~1/3 of matched sibs 60-70% of matched unrelate Higher with mismatched Risk factors HLA disparity, patient age, prior agvhd, graft source TED07_42.ppt 14

15 Chronic GVHD Classification (old but it s s what we ve got) Limited Either or both Localized skin involvement Hepatic dysfunction due to cgvhd TED07_43.ppt Chronic GVHD Classification continued Extensive Generalized skin involvement, or Localized skin involvement and/or hepatic dysfunction due to chronic GvHD OR Liver histology showing chronic aggressive hepatitis, bridging necrosis, or cirrhosis, or Eye involvement (Schirmer test <5mm wet), or Involvement of minor salivary glands/oral mucosa Involvement of any other organ TED07_44.ppt Manifestations Of Chronic GVHD (I) Organ Definite manifestations Possible manifestations System of Chronic GVHD of Chronic GVHD Skin Mucous membranes GI tract Liver Scleroderma (superficial or fasciitis), lichen planus, vitiligo, scarring alopecia, hyperkeratosis pilaris, contractures from skin immobility, nail bed dysplasia Lichen planus, non-infectious ulcers, corneal erosions/nonfectious conjunctivities Esophageal strictures, steatorrhea None Eczematoid rash, dry skin, maculopapular rash, hyperpigmentation, hair loss Xerostomia, keratoconjunctivitis sicca Anorexia, malabsorption, weight loss, diarrhea, abdominal pain Elevation of alkaline phosphatase, transaminitis, cholangitis, hyperbilirubineamia TED07_45.ppt 15

16 Manifestations Of Chronic GVHD (II) Organ Definite manifestations Possible manifestations System of Chronic GVHD of Chronic GVHD Liver GU Musculoskeleta 1/Serosa Hematologic Lung None Vaginal stricture, lichen planus Non-septic arthritix, myositis, myasthenia, polyserositis, contractures from joint immobilization None Bronchiolitis obliterans Elevation of alkaline phosphatase, transaminitis, cholangitis, hyperbilirubineamia Non-infectious vaginitis, vaginal atrophy Arthralgia Thrombocytopenia, esinophilia, autoimmune cytopenias Bronchiolitis obliterans with organizing pneumonia, interstitial pneumonitis TED07_46.ppt Post-TED GVHD TED07_47.ppt Evaluating Post-HSCT Disease Status Most frequent cause of treatment failure Vigilance may affect rapidity of diagnosis Method of detection really does matter TED07_48.ppt 16

17 Method of Detection of Disease Molecular (most sensitive) Blood or marrow Bcr/abl, bcl-2 Cytogenetic (mod. sensitive) Blood or marrow t(9:22), t(14:18) Hematologic (least sensitive) Blood or marrow appearance TED07_49.ppt Post-TED Disease Assessment TED07_50.ppt Indications for DCI Relapse prophylaxis ( planned ) Treatment of relapse: CML, AML Treatment of PTLD, EBV-Lym Treatment of GVHD Treatment of Viral Infections Chimerism Stable or declining donor cells Other emerging indications TED07_51.ppt 17

18 Post-TED DCI TED07_52.ppt Causes of Death after Transplants Done in AUTO Relapse (75%) Organ toxicity (8%) IPn (2%) Infection (6%) GVHD (14%) Other (13%) HLA-ID SIB Relapse (38%) GVHD (14%) UNRELATED Other (9%) Relapse (32%) Infection (17%) IPn (5%) Organ toxicity (13%) Other (17%) Organ toxicity (11%) IPn (7%) Infection (19%) Slide 15 TED07_53.ppt Post-TED Survival TED07_54.ppt 18

19 Late Complications of BMT Regimen-related toxicity Cataracts Neurologic Gonadal Endocrine Growth & development Infection Chronic GVHD Relapse of malignancy/new-2 nd cancers TED07_55.ppt Post-TED Second Cancer TED07_56.ppt Factors Affecting HSCT Success Diagnosis and stage of disease Time from diagnosis to HSCT Quality of HLA match Ages of recipient/donor Prior CMV exposure Disease treatment HSCT protocol TED07_57.ppt 19

20 Observational Database Information on persons treated under ordinary circumstances, with treatments selected by the recipients, by clinical judgements of physicians, or by nature rather than by experimental design. TED07_58.ppt 20