1. Module 1 Haematopoietic stem cell transplantation

2. Learning objectives To understand the difference between allogeneic and autologous HSCT To understand the types of and reasons for the different HSCT conditioning regimens To recognise potential complications associated with HSCT To understand the most common aspects of supportive care and to be able to implement this in clinical practice HSCT, haematopoietic stem cell transplantation

3. Haematopoietic stem cell transplantation Haematopoietic stem cell transplantation (HSCT) –Formerly called bone marrow transplantation (BMT) –Transplantation of multipotent haematopoietic stem cells usually derived from bone marrow, peripheral blood, or umbilical cord blood –Transplanted in order to re-establish haematopoietic function in patients with a damaged or defective haematopoietic system –Patients with malignant cancers require HSCT in order rescue their bone marrow from the toxic effects of chemotherapy –The goal of HSCT in patients with non-malignant diseases is to replace non-functional or failed marrow HSCT is categorised by the donor source –Autologous: from the patient’s own bone marrow –Allogeneic: from another person, related or unrelated, who has been selected as suitably HLA-matched HLA, human leukocyte antigen; IV, intravenous; SCID, severe combined immunodeficiency Saria MG et al. Clin J Oncol Nurs 2007;11:53–63

4. Autologous vs allogeneic HSCT Saria MG et al. Clin J Oncol Nurs 2007;11:53–63; Passweg JR et al. Swiss Med Wkly 2012;142:w13696; American Cancer Society - Stem Cell Transplants. Available at http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/bonemarrowandperipheralbloodstemcelltransplant/stem-cell- transplant-types-of-transplant, accessed February 2014http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/bonemarrowandperipheralbloodstemcelltransplant/stem-cell- transplant-types-of-transplant Autologous transplantationAllogeneic transplantation DefinitionStem cells harvested from patient’s own blood or bone marrow Stem cells provided by a HLA-matched, related, or unrelated donor IndicationsLeukaemias, lymphomas, multiple myeloma Certain types of leukaemia, lymphomas, and other bone marrow disorders AdvantagesNo risk of rejectionDonor cells may attack remaining cancer cells (graft-versus-cancer effect) Disadvantages- Cancer cells may be harvested along with stem cells - Cancer cells may be able to evade immune system - Risk of rejection - Donor cells may attack the patient’s body (graft-versus-host disease) - Increased risk of infection UsesTo bridge haematopoietic failure during high dose chemotherapy for treatment of tumours of the haematopoietic system To replace the haematopoietic system in patients with acquired or congenital failure, and more commonly to exploit the graft-vs-tumour effect

5. Conditioning is required for HSCT Prior to HSCT, patients receive conditioning regimens in the form of chemotherapy with or without radiotherapy Saria MG et al. Clin J Oncol Nurs 2007;11:53–63; Passweg JR et al. Swiss Med Wkly 2012;142:13696; Gratwohl A & Carreras E. Principles of conditioning. In: Apperley J, Carreras E, Gluckman E Masszi T eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. Genova: Forum Service Editore, 2012 pp 122–37 Conditioning regimens for autologous HSCT aim to eradicate the disease Allogeneic HSCT requires conditioning in order to: –Eradicate the disease –Provide immunosuppression to the recipient to prevent rejection due to graft-versus-host reaction –Create a stem cell niche in the bone marrow to allow engraftment of donor cells Histological section of the bone marrow

6. Conditioning regimen types Conditioning regimens play a key role in HSCT, and are required for long-term disease control Traditionally, myeloablative conditioning regimens were used for HSCT Myeloablative regimens destroy the bone marrow, and include: –High-dose (8–10 Gy) total body irradiation –Busulfan and cyclophosphamide chemotherapy These regimens however are associated with significant morbidity and mortality –This led to the development of non-myeloablative and reduced-intensity regimens Gy, Gray (unit of radiation) Shi M et al. Blood Lymphat Cancer 2013;3:1–9 Patient receiving radiotherapy

7. Reduced intensity and non-myeloablative regimens Shi M et al. Blood Lymphat Cancer 2013;3:1–9 Low-dose (2–3 Gy) total body irradiation with or without fludarabine Other chemotherapy drugs, such as busulfan or cytarabine and idarubicin, combined with fludarabine Treosulfan as a substitute for busulfan Novel regimens: Total lymphoid irradiation Monoclonal antibodies Radioimmunotherapy These conditioning regimens have been developed in order to reduce morbidity and mortality

8. HSCT is associated with multiple complications Adapted from Saria MG et al. Clin J Oncol Nurs 2007;11:53–63 Gram-negative bacteria Conditioning regimen toxicities Haemorrhagic cystitis Engraftment syndrome Diffuse alveolar haemorrhage Haemorrhagic cardiomyopathy Pre-engraftment phaseEarly post-engraftmentLate post-engraftment Gram-positive bacteria Aspergillus, Candida Cytomegalovirus infections Varicella-zoster virus Chronic GVHD Idiopathic pneumonia syndrome Haemorrhagic cystitis Acute renal failure (Day 0 = transplant) (Day 30) (Day 100) Weeks after transplant Bronchiolitis obliterans Hepatic veno-occlusive disease Acute graft-versus-host disease (GVHD) 123458121620 Chronology of haematopoietic stem cell transplant complications

9. Neutropenia, GvHD and infection are important complications requiring intervention Complications associated with HSCT require prophylaxis or treatment: GCSF, granulocyte colony-stimulating factor; GvHD, graft-versus-host disease Saria MG et al. Clin J Oncol Nurs 2007;11:53–63; Masszi T & Mank A. Supportive Care. In: Apperley J, Carreras E, Gluckman E Masszi T eds. ESH- EBMT Handbook on Haematopoietic Stem Cell Transplantation. Genova: Forum Service Editore, 2012 pp 156–74 Growth factors (eg GSCF) Immunosuppressive drugs (eg corticosteroids, cyclosporine) Antimicrobials (eg antibiotics, antifungals) Neutropenia GvHD Infection

10. Post-chemotherapy HSCT – requires supportive care Masszi T & Mank A. Supportive Care. In: Apperley J, Carreras E, Gluckman E Masszi T eds. ESH-EBMT Handbook on Haematopoietic Stem Cell Transplantation. Genova: Forum Service Editore, 2012 pp 156–74; Chemotherapy Induced Nausea & Vomiting; A Nurse’s Perspective. Available at http://www.ebmt.org/Contents/Resources/Library/Slidebank/EBMT2013SlideBank/Documents/Nurses/N1239.pdf, accessed February 2014 http://www.ebmt.org/Contents/Resources/Library/Slidebank/EBMT2013SlideBank/Documents/Nurses/N1239.pdf Supportive care Impaired nutritional status Mucositis Nausea Several clinical problems that arise after HSCT frequently require supportive care

11. Summary of HSCT Autologous HSCT uses stem cells derived from the patient’s own bone marrow; allogeneic HSCT uses stem cells from a related or unrelated donor Autologous HSCT has no risk of rejection, however cancer cells may be transplanted along with stem cells Allogeneic HSCT may result in a beneficial graft-versus-cancer effect, although it also carries a risk of rejection and GvHD Conditioning prior to HSCT is required in order to eradicate the disease, prevent rejection, or aid engraftment Reduced-intensity conditioning regimens aim to reduce morbidity and mortality HSCT and conditioning are associated with multiple complications such as neutropenia, mucositis and nausea that require treatment and supportive care

12. Self-assessment questions 1.Of the following, which is not a risk of autologous HSCT? a)Harvesting of cancer cells b)Graft-versus-host disease c)Evasion of transplanted cells by the cancer

13. Self-assessment questions 2.For which three reasons are conditioning regimens required prior to HSCT?

14. Self-assessment questions 3.What is the distinction between myeloablative and non- myeloablative conditioning regimens?

15. Self-assessment questions 4.Immunosuppressive drugs such as corticosteroids are given in order to manage which HSCT-related condition? a)Neutropenia b)Graft-versus-host disease c)Infection

16. Self-assessment questions 5.Of these three clinical problems arising after HSCT, which is most feared by patients? a)Impaired nutritional status b)Nausea c)Mucositis