Objectives. Hematopoietic Stem Cell Transplant. Indications for HSCT. Approaches to Transplant. Define HSCT. Provide overview of HSCT process

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1 Objectives Hematopoietic Stem Cell Transplant Karen Anderson, MN, RN, OCN, BMTCN Seattle Cancer Care Alliance Define HSCT Provide overview of HSCT process Discuss acute complications of HSCT Discuss chronic/late complications of HSCT Indications for HSCT Malignant diseases: Acute and Chronic Leukemia Hodgkin's lymphoma and Non-Hodgkin's lymphoma Myelodysplastic Syndromes Multiple myeloma Selected solid tumors Non-malignant diseases: Hematologic Disorders (ex: Aplastic Anemia, Sickle Cell Anemia) Congenital Immunodeficiencies (ex: SCID, Wiskott Aldrich Syndrome, HLH) Inborn Errors of Metabolism (ex: Hurler s Syndrome) Autoimmune Diseases (ex: Systemic Sclerosis, Multiple Sclerosis) Autologous Approaches to Transplant Allogeneic Related or Unrelated Myeloablative Non-myeloablative 1

2 Stem Cell Sources Advantages Disadvantages Autologous HSCT: An Overview Bone Marrow Peripheral Blood Good source of stem cells Less risk of cgvhd Most abundant source of stem cells Faster Engraftment Anesthesia & surgical risks for donor Longer time to engraftment than PBSC Increased risk of graft failure Growth factors given to healthy donors Higher risk of cgvhd Rationale for Therapy: High doses of chemo and/or radiation are given to treat the disease. The patient s own stem cells rescue the ablated bone marrow. Umbilical Cord Blood Readily available HLA mismatch more acceptable Lack of donor risks Less risk of GVHD Delayed engraftment Smaller dose of stem cells Autologous HSCT: Mobilization and Apheresis Mobilization: A technique used to increase the number of circulating hematopoietic stem cells from the bone marrow into the bloodstream High Dose Chemotherapy + G-CSF ± plerixafor G-CSF Apheresis: The method for stem cell collection using a dialysistype machine with cell separators that are programmed to collect stem cells. Allogeneic HSCT: An Overview Rationale for Therapy: Standard allogeneic: High doses of chemotherapy and/or radiation are used to treat disease. The stem cell infusion rescues the ablated marrow. Also provides a graft versus malignancy effect. Nonmyeloablative allogeneic: Chemotherapy and radiation are given at lower doses that are immunosuppressive and myelosuppressive. The donor stem cells provide a graft versus malignancy effect. 2

3 HSCT Process 1. Planning phase 2. Preparing for transplant 3. Conditioning 4. Transplant 5. Awaiting Engraftment 6. Post-engraftment recovery 7. Long-term follow-up Planning Phase Patient & Donor Planning Oncologist reviews transplant with patient & family Transplant center consultation Address fertility now, if possible HLA type patient & siblings Search the donor registries Other Preparations Assess finances (insurance coverage or pay cash) Select transplant center (statistics on NMDP website) Select a caregiver Make plans for relocation if necessary HLA Typing Degree of compatibility between donor and patient Important HLA markers for HSCT are A, B, C, & DRB1 Matched or mismatched donor options 25% chance that each sibling will be an HLA-match 70% of people do not have suitable family donors Preparative Phase Medical Evaluation Blood Work, Bone Marrow Aspirate & Biopsy, Lumbar Puncture, CT, PET, MRI Oral exam and gynecologic exam Nutritional, Psychosocial, and Spiritual Assessment Chest X-ray, PFTs and Cardiac Studies Family Conference & Informed Consent Process Discussion of protocol and plan, risks and benefits Sign consents Preparation of the Family and Caregiver Orientation to center; Caregiver classes & support groups Central Line Placement 3

4 Chemotherapy Myeloablative Myelosuppressive Conditioning Common Drugs: Melphalan, Fludarabine, Cyclophosphamide, Etoposide, Busulfan Radiation Total Body Irradiation Mini TBI Transplant Stem cell infusion administered like a blood product transfusion Cryopreserved Preserved with DMSO Can cause hemolysis Causes garlic breath Transfusion reactions Fresh Chemotherapy drugs listed w/ exception of busulfan are used off-label for transplant conditioning Awaiting Engraftment Nausea, Vomiting, Diarrhea Mucositis May effect the entire length of GI tract May need PCA & TPN for some length of time Infections Hepatic Sinusoidal Obstruction Syndrome (SOS) Risk factors include TBI, Cytoxan, prior liver disease Can be fatal Engraftment syndrome Fever and rash presents around time of engraftment Graft Failure Allogeneic HSCT: Post Engraftment Recovery Patients are closely followed at the transplant center for several months Acute GVHD and infection are major concerns Seen daily to once/week for medical evaluation and blood tests Management of symptoms Infusion therapy At approximately day +80, patients are completely evaluated for disease state and complications and prepared for discharge home 4

5 Acute Graft vs. Host Disease (GVHD) Donor T lymphocytes (the graft) recognize the antigens and cells in the transplant recipient (the host) as foreign and mount an immunologic attack. Incidence ranges between 35-80%. Predictive Factors for agvhd HSC Source Donor/Host Factors PBSC > BM > UCB Immunomodulation HLA disparity Omission of adequate Parity of female donor agvhd prophylaxis Age of donor and recipient TBI recipients Clinical Features of Acute GVHD Skin (most common) Maculopapular rash, often beginning with palmar/planter surfaces and extending to the face, abdomen and trunk Sunburned appearance to desquamation and loss of skin integrity Gut Anorexia, nausea and vomiting, early satiety Diarrhea, intestinal bleeding and abdominal pain to ileus Liver (rare) Elevated alkaline phosphatase and bilirubin RUQ pain, hepatomegaly and jaundice to ascites and encephalopathy Prevention of agvhd Highest degree of histocompatibility from donor (when multiple donors are available.) Prophylactic immunosuppression methotrexate, cyclosporine, mycophenolate mofetil, tacrolimus, sirolimus Selective T-cell depletion Immunosuppressive drugs listed are used off-label 5

6 Treatment of agvhd Primary Therapy Prednisone 1-2mg/kg/day followed by taper after response (may be given as IV methylprednisone) Secondary Therapy Monoclonal antibodies ATG Sirolimus PUVA (skin) or ECP (skin, liver and gut) Prognosis of agvhd Predicted by grade of agvhd and response to initial therapy Poor responders to treatment have a high-risk of nonrelapse mortality Treatments listed above are considered off-label Allogeneic HSCT: Long-term Follow-Up Follow guidelines from transplant center about safe living with impaired immune function Late complications Chronic GVHD Late infectious complications Pulmonary complications Bronchiolitis obliterans, pulmonary fibrosis Neurological complications Psychological complications Cataracts Sexual disorders (ex: dry vaginal mucosa) and impaired fertility Orthopedic complications Fragile joints due to steroids Secondary malignancy Infections and HSCT Pre-engraftment : HSV, gram negative bacilli, staphylococcus epidermidis, GI-tract streptococci, candida, aspergillus Early Engraftment: candida, staphylococcus epidermidis, aspergillus, CMV, pneumocystis jiroveci Late Phase: CMV, VZV, encapsulated bacteria, aspergillus, pneumocysitis jiroveci 6

7 Immune reconstitution after HSCT Innate immunity usually returns by day 100 Adaptive Immunity: CD4+ helper T-cells numbers may take months to return to normal levels Serum immunoglobulins may take months to years normalize and gain full functionality Immunosuppressants and chronic GVHD further impair immune reconstitution Vaccinations Chronic GVHD Pathophysiology is poorly understood Immune dysfunction T-cells B-cells Fibrotic changes Resembles autoimmune or collagen vascular disorder Predictive factors for cgvhd Clinical Manifestations of Chronic GVHD Previous agvhd PBSC Older donor or recipient HLA disparity Incidence ranges between 30-70% Oral Symptoms Skin Nails Scalp & Body Hair Eyes Genitalia GI Tract Liver Lung Muscles/Fascia/Joints Hematopoietic/Immune 7

8 Treatment of cgvhd Primary Prednisone 1mg/kg/day with a slow taper after improvement usually in combination with: Daily cyclosporine or Daily tacrolimus Salvage Methotrexate Mycophenolate Mofetil Sirolimus Tacrolimus Rituximab Infliximab Pentostatin ECP Supportive Care in cgvhd Infection prophylaxis Symptom palliation Manage dry skin and protect from sun Artificial tears Oral care Gynecology consult Nutritional intervention PT and OT Massage Psychosocial support Treatments listed above are considered off-label Prognosis of cgvhd Mortality in cgvhd is largely attributed to infection. Major morbidity is often present with extensive chronic GVHD and requires longterm therapy. Factors influencing HSCT outcomes Type of disease Disease status at time of transplant Co-morbidities Severity of GVHD Web resources for outcome statistics:

9 Summary HSCT indicated for a variety of malignant and non-malignant conditions, may be only potentially curative option for some conditions Major risks associated with HSCT in the acute and late phases are infection and GVHD Management of treatment side effects for transplant survivors can persist for years Resources: National Marrow Donor Program Understanding Cancer topics Seattle Cancer Care Alliance Questions? Karen Anderson, MN, RN, OCN, BMTCN kcanders@seattlecca.org References Anasetti, C., Logan, B.R., Lee, S.J., Waller, E. K., Weisdorf, D. J., Wingard, J.R., Confer, D.L. (2012). Peripheralblood stem cells versus bone marrow from unrelated donors. New England Journal of Medicine, 367(16), doi: /NEJMoa Appelbaum FR (2007) Hematopoietic-cell transplantation at 50., The New England Journal of Medicine, 357(15), Berger, M., Biasin, E., Saglio, F. & Fagioli, F. (2008). Innovative approaches to treat steroid-resistant or steroid refractory GVHD. Bone Marrow Transplantation,42, S101-S105. Bolanos-Meade, J. & Vogelsang, GB. (2008). Chronic graft-versus-host disease. Current Pharmaceutical Design, 14(20), Brunstein, C.G., Guttman, J.A., Weisdorf, D. J., Woolfrey, A. E., Defor, T. E., Gooley, T. A., Delaney, C.. (2010). Allogeniec hematopoietic cell transplantation for hematologic malignancy: Relative risks and benefits of double umbilical cord. Blood, 116, doi: /blood Confer, D.L. (2000). The National Marrow Donor Program: Meeting the needs of the medically underserved. Cancer, 91(S1), Ferrara, J.L.M., Levine, J.E., Reddy, P., & Holler, E. (2009). Graft-versus-host disease. The Lancet, 373, Ferrara, J. L. M., Levine, J. E., Holler, E., & Edinger, M. (2012, November/December). Recent advances in acute graft-versus-host disease. The Hematologist, 9(6) 5 & 15. Retrieved from 9

10 References Filipovich, A. H., Weisdorf, D., Pavletic, S., Socie, G., Wingard, J. R., Lee, S.J., Flowers, M. E. D. (2005). National Institutes of Health consensus development project on criteria for clinical trials in chronic graftversus-host disease: I. Diagnosis and Staging Working Group Report. Biology of Blood and Marrow Transplantation; 11(12), Flowers. M, Inamoto, Y., Carpenter, P., Lee, S., Kiem, H., Petersdorf, E.Martin, P. (2011) Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria. Blood, 117(11): Fraser CJ, Bhatia S, Ness K, et al. (2006). Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: A report from the Bone Marrow Transplant Survivor Study. Blood,108(8): Gooley, T.A., Chien, J.W., Pergam, S.A., Hingorani, S., Sorror, M.L., Boeckh, M., McDonald, G.B. (2010). Reduced mortality after allogeneic hematopoietic-cell transplantation. New England Journal of Medicine, 363(22), doi: /NEJMoa Gragert L, Eapen M, Williams E, Freeman, J., Spellman, S. Baitty, M., Maiers, M. (2014). HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. New England Journal of Medicine, 371(4): Horowitz, M.E. & Sullivan, K.M. (2006). Chronic graft-versus-host disease. Blood Reviews, 20, Jagasia, M., Arora, M., Flowers, M. E.D., Chao, N.J., McCarthy, P. L., Cutler, C. S., Hahn. T. (2012), Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood, 119; ; doi: /blood Jaksch, M. & Mattsson, J. (2005), The pathophysiology of acute graft-versus-host disease. Scandinavian Journal of Immunology, 61: doi: /j x Laffan, A. & Biedrzycki, B. (2006). Immune reconstitution: The foundation for safe living after an allogeneic hematopoietic stem cell transplantation. Clinical Journal of Oncology Nursing, 10(6), Lee, S. J., & Flowers, M.E. D. (2008). Recognizing and managing chronic graft-versus-host disease. ASH Education Book, vol (1), doi: doi: /asheducation References Min, C.K. (2011). The pathophysiology of chronic graft-versus-host disease: the unveiling of an enigma. The Korean Journal of Hematology, 46(8), doi: /kjh National Marrow Donor Program Information for Patients and Physicians. Schmid, I., Stachel, D., Pagel, P., & Albert, M.H. (2008). Incidence, predisposing factors, and outcome of engraftment syndrome in pediatric allogeneic stem cell transplant recipients. Biology of Blood and Marrow Transplantation, 14(4), doi: /j.bbmt Socié, G. (2011). Chronic GVHD: B cells come of age. Blood 117 (7), doi: /blood Thomas, ED. (1990). Bone Marrow Transplantation-Past, Present & Future. Nobel Lecture. Weisdorf, D GVHD- The Nuts & Bolts. Hematology, 2007, Weisdorf, D, (Ed.). (2008) The National Marrow Donor Program reports to the community on 20 years of unrelated donor hematopoietic cell transplantation. Biololgy of Blood and Marrow Transplantation;14(9, Suppl. 3): Westin, J. R., Saliba, R.M., De Lima, M., Alousi, A., Hosing, C., Qazilbash, M. H., Couriel, D. R. (2011). Steroidrefractory acute GVHD: Predictors and outcomes. Advances in Hematology, volume 2011, 8 pages. 10