HOW TO TREAT 21
ausdoc . com . au 10 MAY 2024
HOW TO TREAT 21
HLA matching in many clinical situations , a fully matched unrelated donor transplant is now often equivalent to a matched sibling transplant . Depending on the clinical urgency , a less than fully matched related or unrelated donor may be chosen . As a generalisation , it may be considered that in the matched unrelated donor transplant setting , the survival probability reduces by about 10 % for each mismatched allele . 10
A third choice is a haploidentical donor — a parent , sibling or child who shares half of the recipient ’ s genome . Haploidentical transplant is associated with higher risk of GVHD , graft rejection or both . This type of donor is often used when a matched unrelated donor is not available , or when greater GVD effect is desired such as in higher risk disease .
TYPES OF STEM CELL SOURCE Stem cells may be collected from bone marrow , peripheral blood or umbilical cord blood . Bone marrow collection , initially the main source of stem cells , is invasive as it involves multiple marrow punctures and is usually performed under general anaesthesia . Many adult transplants are now performed using peripheral blood stem cells collected by apheresis after a 4-5 day course of G-CSF . Bone marrow collection remains the standard of care in children and in non-malignant diseases .
Umbilical cord blood ( from private cord blood collections or cord blood banks ) contains high numbers of stem cells per volume and may be used in patients who do not have a matched unrelated donor . Cord blood transplantation is associated with a lower risk of severe GVHD , though does have a slower cell count recovery . In recent years there has been a decline in the number of cord blood transplants because of the increased use of haploidentical donors .
Process
PRE-TRANSPLANT WORKUP It is important to assess a patient ’ s suitability for transplantation , as proceeding to transplant in a patient who is unfit is likely to cause harm without significant benefit .
Key considerations include the patient ’ s current level of function , their disease remission status , comorbidities and mental health . There are several scoring systems for assessing transplant suitability , such as the haematopoietic cell transplantation-specific comorbidity index , disease risk index and the European Society for Blood and Marrow Transplantation ( EBMT ) risk score . 11-13 Each patient is discussed in a multidisciplinary team meeting to identify potential barriers to transplantation .
Patients are provided with counselling regarding the risks and potential benefits of allogeneic stem cell transplant . Though the goal might be to cure , there are significant risks of disease progression , relapse , complications and altered quality of life .
DONOR SEARCH AND LOGISTICS Despite many donors worldwide , there is inequity in matched unrelated donor searches . Caucasian
Box 1 . Indications for autologous stem cell transplants
• Multiple myeloma :
— Autologous transplant with high-dose melphalan conditioning is a routine part of first-line treatment for eligible patients with multiple myeloma following induction therapy .
— The goal of transplant is to maintain the patient in a diseasefree state for as long as possible ; in a major study the five-year progression-free survival was 55 %, compared with 45 % in patients who did not have a transplant . 1
— Autologous transplantation also has a role in certain patients with relapsed myeloma , light chain amyloidosis and POEMS ( polyneuropathy , organomegaly , endocrinopathy , monoclonal protein , skin changes ) syndrome .
• Relapsed / refractory lymphoma : — Autologous transplant may be considered in patients with both relapsed low-grade and high-grade lymphomas . — Typically , this is reserved for patients who remain sensitive to chemotherapy after their first relapse .
— One study of patients with relapsed diffuse large B-cell lymphoma ( associated with poor prognosis ) reported an overall survival rate at four years of 61-65 %. 2
• Other indications : — Suitable patients with certain relapsed solid organ malignancies , such as testicular cancer , may also be offered autologous transplantation .
— There is ongoing evaluation of its role in certain rapidly progressive autoimmune diseases including MS , systemic sclerosis and Crohn ’ s disease .
Box 2 . Indications for allogeneic transplantation
• Acute leukaemia : — Allogeneic transplant in acute leukaemia is indicated in patients with intermediate or high-risk disease , persistent measurable residual disease after initial treatment , transformed or treatment-related leukaemia , and relapsed leukaemia .
• Other myeloid neoplasms : — Allogeneic transplant is a treatment option for high-risk myelodysplastic syndrome .
— Transplant is the only option for curing myelofibrosis , while in the other myeloproliferative neoplasms it is reserved for high risk or refractory disease .
• Relapsed / refractory lymphoma : — Allogeneic stem cell transplant is typically reserved for patients with diffuse large B-cell lymphoma or Hodgkin ’ s lymphoma that have relapsed following autologous stem cell transplant .
• Other indications :
— Allogenic transplant is indicated for bone marrow failure syndromes such as severe aplastic anaemia as well as certain other congenital disorders such as sickle cell disease , thalassaemia major , inborn errors of metabolism and primary immunodeficiency syndromes .
patients globally have an approximately 75 % chance of finding a donor , which reduces to 27 % in South Asian patients and 19 % in patients of African descent . 14 Efforts are being made to address this disparity by improving the genetic diversity of donor pools .
It is important to consider the ethical implications when gaining consent from a donor . Stem cell mobilisation in healthy donors is not without risk ( albeit small ), including potential cardiovascular , thrombotic and pulmonary complications . 15 Donors who are related to the recipient may be pressured to proceed with donation . 15
The donor is assessed for physical fitness and the type of collection ( peripheral blood vs marrow ) is determined . Depending on donor location , harvested cells may be delivered ‘ fresh ’ to the transplant centre or cryopreserved for shipping .
CONDITIONING In patients with malignancies , conditioning therapy has two aims . The first is to ( attempt to ) eradicate the underlying malignancy and secondly , recipient immunosuppression , to reduce the risk of immune-mediated rejection ( host vs graft ). There are several broad types of conditioning therapy . Myeloablative conditioning is designed to eradicate residual patient haematopoiesis and is typically used in younger patients . Non-myeloablative conditioning and reduced intensity chemotherapy are associated with significantly less toxicity and are used in older or more infirm patients . Specialised conditioning is used for cord blood and haploidentical transplants . Conditioning may include chemotherapy , radiotherapy , monoclonal antibodies and targeted therapy .
REINFUSION The cells are checked before reinfusion , to ensure viability and provide a stem cell count . Reinfusion of cells is a relatively quick process and is associated with few side effects .
ENGRAFTMENT Patients remain in hospital after reinfusion for close monitoring and supportive care . Time to engraftment ( neutrophils greater than
0.5x10 9 / L for three consecutive days ) is highly variable ( may take 10-21 days ) depending on the stem cell source , the dose of cells given and the use of G-CSF .
Indications
Haematopoietic malignancies constitute the major indications for allogeneic transplantation ( see box 2 ).
Post-transplant care and complications
SUPPORTIVE CARE A central venous catheter is inserted to allow for frequent blood collections and to provide multiple infusions concurrently . Patients are isolated in a single room because transfusion of blood products ( red cells and platelets ) is almost always required . Finding appropriate blood products may be complicated by the need for irradiated products ( used to prevent transfusion-associated GVHD ) compatible with both the donor and recipient .
Regular mouth care assists with limiting oral mucositis and intensive nutritional support , up to total
parenteral nutrition , is provided as patients are at high risk of malnutrition . Psychological support is provided to patients who require it .
INFECTIVE A wide range of infective complications may occur following allogeneic transplantation because of the depth of immunosuppression . Febrile neutropenia and other bacterial complications typically occur before engraftment , and patients are also at risk of viral infections including herpes simplex , varicella – zoster , Epstein-Barr , CMV , influenza , COVID-19 , BK virus and JC virus infections . Profound immunosuppression confers the risk of severe invasive fungal infections , and less commonly , protozoal infections .
Close involvement of infectious diseases physicians is required to ensure appropriate treatment .
Allogeneic transplant patients receive prophylaxis against pneumocystis , herpesvirus , CMV and fungal infections . Febrile neutropenia is treated through rapid initiation and rationalisation of protocolised broad-spectrum antibiotics . Patients start a staged program of revaccination against a variety of infectious diseases six months post-transplant .
GRAFT VERSUS HOST DISEASE GVHD is a complication of haematopoietic stem cell transplant ( and , rarely , following solid organ transplantation and blood transfusion ). This occurs when immune cells from the donor recognise the recipient ’ s antigens as foreign , resulting in an immune reaction .
Acute GVHD typically occurs within the first 100 days of transplant . This condition commonly affects the skin ( see figures 3 and 4 ), gastrointestinal tract and liver . The mainstay of management is steroid treatment , though prevention using immunosuppression is key .
Chronic GVHD occurs in 30-70 % of cases and can affect many organ systems including the skin , nails , mouth , gut , liver , eyes , lungs , salivary / lacrimal glands , musculoskeletal system and immune system . 16 Chronic GVHD is associated with a higher risk of infection and overall poorer quality of life . First-line treatment is typically with steroids ; second-line therapies ( with varying efficacy ) include ruxolitinib and extracorporeal phototherapy .
Calcineurin inhibitors such as cyclosporin or tacrolimus are typically used for GVHD prophylaxis ; these are carefully titrated by monitoring drug levels and the patient ’ s clinical status . High-dose methotrexate , mycophenolate or antithymocyte globulin may also be provided for GVHD prophylaxis . Rates of GVHD remain high despite these measures , and further research is needed in this field .
ASSESSING GRAFT AND DISEASE STATUS Following the patient ’ s recovery , a bone marrow biopsy or further
Close involvement of infectious diseases physicians is required to ensure appropriate treatment of transplant patients . imaging is performed to assess for disease remission . Chimerism studies assess the percentage of donor and recipient DNA within white cells .
OTHER COMPLICATIONS Conditioning treatment may cause a range of acute complications including mucositis , pancytopenia , organ dysfunction , gastrointestinal toxicity and haemorrhagic cystitis . Failure to engraft with no recovery in cell counts following allogeneic transplant is rare and often fatal . During recovery of cell counts , an engraftment syndrome may occur similar to that in autologous transplant . Allogeneic transplant is also associated with several disorders of endothelial dysfunction including sinusoidal obstructive syndrome , thrombotic microangiopathies and capillary leak syndrome .
Patients may relapse following transplant ; this depends on several factors including type of disease , disease status before transplant and the amount of GVD effect allowed . Longer-term , patients are at increased risk of metabolic and cardiac diseases following transplant , including type 2 diabetes mellitus ( 8-41 %), dyslipidaemia ( 9-61 %) and cardiovascular disease ( 5-10 %). 17
Secondary malignancies may occur . Post-transplant lymphoproliferative disorder refers to the development of lymphoma or a non-specific lymphoproliferative disorder in the context of immunosuppression following transplantation . Secondary therapy-related or donor-derived myeloid malignancies such as myelodysplastic syndrome or acute myeloid leukaemia may occur . Patients are also at increased risk of solid organ malignancies . The overall risk of second malignancy at 10 years following allogeneic stem cell transplant is approximately 6 %. 18
Other long-term PAGE 24