Stem cell transplantation
MHC § Chromosome 6 § Class I § Expressed on the surface of nearly all cells § Present antigens to CD8 + T cells § Heavy chain and B2M § A, B and C (C initially not typed for but subsequently found that mismatching at C locus increased GVHD) § Class II § Only expressed on APCs, B cells and monocytes § Alpha, beta, gamma and delta chains § DR (invariant alpha chain with highly polymorphic beta region) § DP and DQ § Class III § Not thought to be important in transplantation
HLA typing § Low resolution § PCR using short sequence oligonucliotide probes (SSOP) § Highly automated § Used for registry typing and sibling matches as well as typing for HLA matched platelets
§ High resolution § Now done by sequencing
§ Japanese – little HLA polymorphism cf Africa
§ Minor antigens are expressed on the surface of the cell as degraded peptide bound to HLA molecules
§ Synergenic transplant – monzygotic twins
§ Allogenic transplant § Most groups will use 5/6 matched donors (Higher GVHD but lower relapse) § Mismatches tolerated better by younger patients
Stem cell source Peripheral blood SCT § Possible survival benefit (eg 66% v 54%) § Lower TRM - more rapid engraftment (more committed progenitors collected) § Relapse rates lower § Higher GvHD (acute 64 v 57% / chronic 46% v 35%) § May be superior for patients with advanced malignancy but worse for non-malignant transplantation
§ Lymphocyte depletion § Leads to lower rates of GVHD but increased relapse
Cord blood § Cells collected from the umbilical cord after delivery § Over 100,000 units stored to date § Available quickly – 2 weeks cf 2 months for an allograft § Limited by the size of the unit § Rates of acute and chronic GVHD lower § No possibility of DLI
Unrelated bone marrow transplant § Donors can be found for most patients with common haplotypes § Afrocaribean patients very difficult to match as have very polymorphic HLA backgrounds § Graft failure and GVHD more common than in sibling transplantation
Autologous transplantataion § No need for donor searches § Potential tumour contamination § SCTs with tumour DNA detectable by PCR result in a higher relapse rate in t(14;18) B cell lymphomas § PBSCT has similar contamination to BMT – lower concentration of cells but this is compensated by the higher dose of cells
Reduced intensity allografts § Aim is to expoit GVL effect without the toxicity of full myeloablative conditioning § Possible to achieve mixied chimerism in patients who have received previous intensive myelosuppressive chemotherapy with minimal preparative toxicity § If patients have had little previous chemotherapy (MDS or myeloma) then more intensive regimes using purine analogues are required § Patients who fail to engraft usually have an autologous recovery § Antitumour responses in diseases where there is a strong GVT effect § GVHD rates often higher than in conventional transplantation and may be fatal § Chimerism determined using sex differences using FISH or analysis of variable number of tandem repeats (VNTRs)
Indications for SCT 1. Dose intensification for responsive tumours § Not useful for most solid tumours as there is not a steep dose-response curve 2. Graft verses leukaemia effect 3. Correction of stem cell defects a. Fanconi’s b. Haemoglobinopathies 4. Correction of immuneodeficiencies a. SCID 5. Gene therapy a. Eg Hunter’s syndrome where haemopoiesis is normal but allogenic SCT provides a continous source of enzyme replacement therapy b. The use of genetically altered stem cells has proven more difficult than initially hoped and the effort has now largely stalled 6. Autoimmune disease a. Autologous SCT b. May be useful in rheumatoid arthritis, SLE, systemic sclerosis and MS
Graft versus tumour effect § Thought to be due to NK and cytotoxic T cells § CTLs recognise alloantigens via MHC class I § NK cells recognise and kill tumours or virally infected cells that have down regulated MHC class I expression § KIRs (killer inhibitory receptors) recognise HLA class I and prevent killing
Transplant for specific diseases CML § Prior to imatinib patients were routinely transplanted § Patients in accelerated phase or blast crisis should received imatinib in an attempt to bridge them for transplant § Responses are generally short lived and should not deter transplantation § Five year survival figures for transplantation depend on scores for risk factors (donor type, disease stage, age, sex combination and time to transplantation) falling from 72% to 60% to 40% to 20% for 0 v 2 v 4 v 6 risk factor points. § Thus transplant may be the best initial option for patients under the age of 40 with a matched sibling donor.
Aggressive NHL § Autologous stem cell transplantation § Superior survival over conventional chemotherapy (46% v 12%) § Best option for relapsed chemotherapy sensitive lymphoma § Transplantation in first CR does not seem to be of benefit for high grade lymphoma
Indolent lymphoma § Autologous transplantation § Patients with PCR negative marrows for t(14;18) at transplant had longer tumour-free survival § PCR positive marrows can be converted into negative by purging § Heavily pre-treated patients had high rates of MDS post autograft § GITMO trial 84 v 67% 4 year survival with transplant § Rituximab may be helpful in autologous transplant § Y90 labelled antiCD20 may be helpful in preparative regimes
Hodgkin Disease § Autologous SCT is accepted therapy for patients with early relapse after chemotherapy for Hodgkins § Improved survival also reported for Hodgkin’s disease § Allogeneic transplant not thought to have a survival advantage compared to autologous SCT since GVL effect offset by the increased morbidity
Myeloma § Early autologous SCT confers a 12-18 month survival advantage over chemotherapy alone § Allografts may cure disease § DLI can induce second remissions in 40-60% of patients who relapse after allograft
AML § Treatment option for patients in first CR § Children with a matched sibling routinely receive allogeneic transplants after induction § Adults – allogenic transplant in first remission is usually reserved for those with high risk features of AML § Consolidation therapy prior to transplant does not seem to improve results § Primary refractory disease § Very low long term survival (10%) and should be considered for novel transplant strategies § Relapsed AML § Patients in second CR have a survival rate of approximately 30-40% § DLI 15% achieve long term remission § Autografting can be used as consolidation therapy
ALL § Offered to poor risk patients (cytogenetics t9;22, t4;11, t1;19) in CR1 § 30-50% survival if transplanted in CR1 § 5-20% survival if transplanted beyond CR2 or in relapse § Less GVL effect in ALL compared to AML § Generally offered to standard risk patients in CR2 if reinduction can be achieved § Very high rates of relapse if transplanted in relapse § Children with relapsed disease may do better if transplanted (particularly the early relapse group
Autoimmune diseases § Autologous transplantation has been performed in a variety of autoimmune diseases § Transplant related morbidity and mortality – often organ dysfunction due to AI disease worsens during transplant § Trials considered encouraging in the transplant literature have generally been considered disappointing in the rheumatology literature
Aplastic anaemia § No trials have directly compared SCT with immunosuppression § Need to establish diagnosis first § Fanconi’s anaemia highly sensitive to alkylating agents and transplant can be performed with using reduced intensity regimes § Sensible to tissue type the patient and any siblings early § For young patients with super-severe aplastic anaemia many centers would move straight to transplantation urgently to minimise sensitisation with transfusions § If the patient has significant infections transplant offers the most rapid approach to neutrophil recovery
Haemoglobinopathies § Thalassaemia § Outcome related to iron chelation and hepatic fibrosis § If neither present overall survival 94% with recurrence of thalassamia in 6% § If iron accumulation has already occurred then overall survival drops to around 60% § Interestingly if the patient has had more than 100 units of blood the chances of rejection fall and a redcuced intensity regime may be used § Bone marrow may be preferred rather than peripheral blood to reduce the risk of GVHD § Patients often have mixed chimerism § Sickle cell disease § Difficulty predicting clinical course for the patients § Children with significant risk often not identified until they have end organ damage § Difficult to identify suitable unaffected sibling donors (only available for 14% of patients in one study) § Over 90% survival with over 85% being disease free § Results from a Belgian study suggest that if the patients are transplanted very early (<4 blood transfusions) they have a better outcome. § Mixed chimersism develops in some patients (similar to thalssaemia)
Immune deficiency § New borns identified as at high risk of SCID should be isolated at birth – infection increases the TRM § Definitive diagnosis is important so that the natural history of the disease can be established and the intensity of the transplant conditioning tailored (determined by lymphocyte and NK cell function) § In some forms of SCIDS such as Jak3 deficiency the patient is unable to reject stem cells and a simple infusion is all that is required § However often don’t regain B cell function unless there is chemotherapy given § Survival best for matched sibling transplants with a 70-100% survival § Falls to 50% when there is no sibling donor § Either cord transplant (always CMV and EBV neg) or a hapling allograft from one of the parents
Metabolic disorders § Role of transplant varies with the disorder (not effective for Niemann-Pick for example) but others such as Hurler and Hunter syndromes have been successfully treated with SCT. § In some cases donor heterozygosity will not cure the disease (making transplant from the parents / siblings difficult) § Possible to do IVF with embryos lacking the mutation and being HLA identical
Paediatric solid tumours § Better outcome in neuroblastoma and Ewing’s sarcoma with autografting Solid tumours § Renal carcinoma – allografting may be helpful as may be susceptible to graft verses tumour effect § Breast cancer § Metastatic cancer - high dose therapy with autologous stem cell therapy does not seem to be of benefit. § Dutch study has suggested that very high risk subsets (stage II or III disease with 10 or more positive lymph nodes) do better with autologous SCT (61 v 51% relapse free survival)
General transplant issues
Venoocclusive disease § 10-60% of patients § Chemotherapy induced damage to endothelial cells, sinusoids and hepatocytes in the area surrounding terminal hepatic venules. § May also occur in the lung § Risk factors § Previous hepatocellular damage at the time of transplant § Previous heavy treatment § High busulphan levels § >10-12 Gy TBI § Clinical features 8-10 days after the start of chemotherapy § Tender hepatomegaly § Weight gain / ascites § Jaundice § Investigations § US Doppler – hepatic and arterial flows § Transjugular liver biopsy – definitive diagnosis § Treatment § Defibrotide § 36% complete resolution in one study § Polydeoxyribonucleotide with multiple antithrombotic and fibrinolytic activities § Little systemic anticoagulation § Heparin and tPA – 30-40% response rate but significant increased risk of haemorrhage
Thombotic microangiopathy § Most common after allografts § Presents like TTP § Difficult to diagnose § Appears to be related to cyclosporine toxicity and responds to stopping cyclosporine § Often fulminant and has a very high mortality § Sepsis and acute GVHD appear to be the root cause § No response to plasma exchange
Haemorrhagic cystitis § Cyclophosphamide toxicity if early § Viral infection if occurs late
Acute GVHD § Onset is periengraftment § Due to a combination of T and NK cell infiltration § Thought that initial cytokine release § Risk factors § Increasing age § HLA mismatched graft § MUD allografts particularly from parous females § Clinical features § Erythemoatous rash (starting on face, sparing scalp, palms and soles) § Diarrhoea § Elevated bilirubin § Grading system (Glucksberg) § Overall grade = worst score
§ Prevention § Lymphocyte depletion of the graft § Increases graft rejection rates and increases relapse rates § Cyclosporin (+/- methotrexate) § Treatment § Methyl pred 1-2mg/kg § Infliximab / anti Il2 / ATG / dacluzimab
Chronic GVHD § 40-80% of allograft survivors § Increasing as older patients being allografted and increasing use of PBSCT § Risk factors § Acute GVHD § Older age § PBSCT § Second transplants § DLI § Two models of pathogenisis § Late allogenic activity § Analagous to spontaneous human autoimmune disorders, particularly scleroderma § Clinical features § Skin § Eyes - dry § Mouth – dry mouth with erythema, lichenoid changes and ulceration § Liver – elevated bilirubin or ALP § Fascia – reduced range of movement of skin bound to fascia – often similar to scleroderma § Virtually every other autoimmune disorder is described in patients with chronic GVH § Major cause of death is infection § Prophylactic antibiotics / IVIg if immunoglobulin levels low § Treatment § Steroids § Cyclosporin § Psoralen + PUVA
Relapse § DLI § CML 80% chance of achieving CR after DLI § Myeloma 40-60% § Acute leukaemia 15% long term disease free survival
Late complications § Endocrine effects § Thyroid dysfunction § Gonadal function impaired § Children have benefited from growth hormone therapy § Steroid side effects – osteoporosis / avascular necrosis § Cognative effects § IT MTX § Parents tend to underestimate childs quality of life and functional ability § Secondary malignancy § MDS § 7% after autologous transplantation for NHL in one study – rates normally thought to be lower than this § Other secondary tumours including leukaemia
Stem cell harvest § Similar to blood processing § SOP § Donor must be counselled and consented § Medical examination ECG / CXR / anaesthetic assessment if bone marrow harvest under GA § Tested for viruses § HIV § Hepatitis B and C § HTLV1 § CMV § Differing methods used § Bone marrow harvest – under GA § Peripheral blood stem cell harvest § GCSF alone § Allogenic donors § Autologous donors who have had little exposure to previous chemotherapy § Cyclophosphamide and GCSF § Used widely world wide particularly in patients with myeloma § Etoposide and GCSF § Used in patients highly pretreated with alkylating agents eg. Lymphoma autografts since these patients don’t seem to mobilise well with cyclophosphamide § Used with acetazolamide (to prevent metabolic acidosis) and methylpred to reduce side effects § Harvesting is usually performed on day 13 or 14 following chemotherapy depending on the CD34 count
Matching § Male better than female § HLA DR worst mismatch § Younger patients in good health § CMV status (to match recipient) § Blood group
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