Splenectomy

  1. All patients should receive pneumococcal, HiB, meningococcus group B and influenza vaccine at least 2 weeks prior to the elective splenectomy
  2. Strong consideration for life long prophlyactic penicillin V 250mg BD
  3. organise medialert bracelet

Chronic Lymphocytic Leukaemia

Presentation:
  • Routine FBE (lymphocytosis > 5 x 10^9/L0 in 25%, with immunophenotype showing CD5+/ CD19+, CD23+
  • Lymphadenopathy and organomegaly
  • Cytopenias and transfusion dependence
  • Infection secondary to relative immune paresis
  • B symptoms (Rare)
  • Immune: auto-immune haemolytic anaemia (15 - 30% have DAT+ haemolytic anaemia), ITP
  • Severe catastrophic event of richter's transformation --> large cell transformation with bone symptoms, painful, rapidly enlarging intra-abdominal mass, rapid and unexpected rise in LDH
Investigations:
  • Lymphocytosis, cytopenias
  • Flow cytometry: CD 19/5, Ig(weak), CD23
  • DAT
  • LDH, beta 2 microglobulin = prognostic markers
  • Uric acid, calcium
  • Bone marrow aspirate and biopsy – not always performed
  • +/- CT scan
Staging & prognosis:
  • Binet. The other staging system is Rai, but I like to use Binet as it is easy to memorise
    • Stage A: ≤  2 nodal regions
    • Stage B: > 2 nodal regions
    • Stage C: anaemia +/- TCP
  • Serum LDH and beta2-microglobulin
  • Unmutated IgH
  • Zap70
  • Number of adverse chromosomal abnormalities eg del 17p
Management
  • Do nothing: may observe patient, especially if elderly with multiple comorbidities as they may not be able to tolerate chemotherapy
  • Treatment to be considered if Binet stage B or C, progressive disease, AIHA, ITP, frequent infections
  • If elderly but minimal co-morbidities consider chlorambucil based regimes
  • For younger patients chemotherapy is indicated with fludarabine based regimes [fludarabine causes myelosupression] --> put into a deep and prolonged admission to prolong overall survival (most commonly used agent in CLL)
  • Rituximab now often used in the protocol
  • Other monoclonal antibodies are being used: 
    • Ofatumumab (anti-CD20) - evidence for the use in maintenance in relapsed CLL
    • Ibrutinib - Ibrutinib was better tolerated and resulted in higher response rates and superior rates of progression-free and overall survival at two years in accordance to the RESONATE 2 trial N Engl J Med. 2015;373(25):2425.

Myelodysplastic syndrome

Presentation:
  • Usually as a consequence of cytopenias
  • Transfusion dependence
  • requirement for iron chelation therapy
  • Transformation into AML
Risk factors
  • Age >65
  • Previous chemotherapy or radiotherapy (secondary MDS worse prognosis)
Investigations
  • FBC shows cytopenias, may have macrocytosis
  • BM Biopsy may show ringed sideroblasts, specific morphology, blasts <5%, to diagnose you need BM dysplasia affecting 10% of a specific myeloid lineage
  • Flow cytometry
  • Cytogenetics, eg del 5q, complex karyotype
  • Mutational analysis (eg SF3B1)
Staging:
  • Based on IPSS-R score
    • cytogenetics
    • % blasts in bone marrow
    • Cytopenias
      • Hb
      • Plt
      • Absolute neutrophil count
Management
  • Supportive
    • MDS support groups
    • Transfusion dependence - organising transport to hospital to facilitate this
    • Fe chelation therapy if at risk of Fe overload
    • G-CSF in consultation with haematologist
    • Palliative care involvement
  • Specific therapy
    • Azacitadine if IPSS-R high risk - RCT showed that azacitadine results in increased overall survival
    • lenalidomide for del(5q), 60% transfusional independence
    • Allograft if young

Bone Marrow Transplantation

History
  • Indication for the SCT
  • Autologous or allogeneic
    • Who was the donor (only ~30% of Pts have an HLA-compatible relative)
    • What was the HLA match – matched at 8 sites (A, B, C and DR)
  • HLA genotyping
    • HLA loci are located on chromosome 6
    • Divide these alleles into Class I and Class II alleles
    • Class I: A, B and C group antigens – many different alleles
    • Class II: DP, DQ, DR
    • Parents of any particularly individual will carry mixture of these two allelic groups
      • Each child will have a mixture of haplotypes from mother and father
      • Each sibling has a 25% chance of being a match to any other siblings
    • If unable to find a match sibling – unrelated donor
    • Either described as
      • 8/8 match: match on A, B, C and DR antigens
      • 10/10 match: + DQ
  • Source
    • Mobilised peripheral blood stem cells
    • Cord blood
    • Bone marrow
  • What kind of conditioning chemo was used
    • Myeloablative - wipes out the marrow completely, if engraftment does not take place then patient effectively has bone marrow aplasia
    • Reduced intensity - wipes out marrow but will recover if engraftment does not occur
  • How long was the patient in hospital after transplantation
  • Social impacts - esp fertility, prognosis, symptom control now
  • Transplant-associated problems:
    • Mucositis
    • GVHD - maculopapular rash + pruritus, raised ALP and bili with normal transaminase, GI with watery diarrhoea
      • Prevalence of acute GVHD is directly related to the degree of mismatch between HLA proteins.
        • It ranges from 35–45% in recipients of full-matched sibling donor grafts and to 60–80% in people receiving one-antigen HLA-mismatched unrelated-donor grafts. 
    • Infection - stages based on timeframe: First 3-4 weeks (neutropaenia): bacterial +/- fungal; Next 2 months: CMV, EBV, BK virus, RSV and other viruses, Day 100 +: encapsulated bacteria, VZV, PJP, aspergillus, toxoplasmosis
    • Immunosuppression – osteoporosis, diabetes
    • Relapse
    • Secondary malignancy – especially skin cancers, PTLD
  • Current medications for immunosuppression to decrease risk of GVHD
Examination
  • Cushing appearance
  • Cytopenias: anaemia, thromboctyopenia
  • Eyes: CMV retinitis
  • Signs of GVHD - skin changes similar to scleroderma, dry eyes, dry mouth, alopecia, bronciolitis obliterans
  • Veno-occlusive disease of the liver - hepatic enlargement
  • full haematological examination
  • Herpes zoster
Post Transplant Supportive Treatment
  • Transfusion support – irradiated blood and platelets, CMV negative if CMV negative recipient
  • G-CSF – to support engraftment and speed recovery
  • GVHD prophylaxis in allo transplant –
    • Combination of pred + methotrexate +/-cyclosporine (increased risk if previous blood product exposure, previous pregnancy)
  • Infection prophylaxis
    • CMV - ganciclovir/ valganciclovir prophylaxis especially if CMV positive. Use seronegative or filtered blood products if CMV -ive to reduce the number of leukocytes (and reduce risk of CMV infection)
    • Fungal – fluconazole or posiconazole
    • PCP – Bactrim/ pentamadine for 12/12 for allo and 6/12 for auto
Management of complications
  • Mucositis - sodibic mouthwash, local anaesthetic, systemic analgesia, screen for HSV and treat with aciclovir if present, nilstat
  • Infection: commence antimicrobial prophylaxis, ensure vaccinations are up to date
  • Cytopenias - manage with transfusional support
  • acute GvHD: Immunosuppression with methylprednisone + cyclosporine, Steroid refractory GVHD Rx with Rituximab, ATG, alemtuzumab (anti-CD52) = RAA
  • Hepatic Sinusoidal Obstructive Syndrome - hepatomegaly, RUQ pain, Jaundice, Ascites: associated with myeloablative conditioning, investigations reveal elevated aminotransferases and bilirubin.
    • Use defibrotide Blood. 2016;127(13):1656.
  • Chronic GvHD - 100d +, similar to scleroderma in skin thickening, can involve any organ. Rx with prednisolone
  • Infertility - pre Rx requirements for sperm banking, GnRH agonists as ovarian protection, embryo freezing 
  • Secondary malignancy - 8% incidence at 20 years, Pts need to undertake age appropriate cancer screening

Multiple Myeloma

History
  • ECOG status
  • Symptoms of cytopenias:
    • Anaemia
    • Infections
    • Bleeding
  • Bone pain and fractures
  • Fatigue
  • Weight loss
  • Symptoms of hypercalcaemia
  • Renal failure
Risk factors
  • Agricultural workers
  • Radiation
  • Benzene
  • Obesity
  • Blacks
Diagnosis and Investigations
  • Myeloma defined as:
    • clonal bone marrow >10% or biopsy proven extramedullary plasmacytoma and myeloma defining event (CRAB) OR
    • clonal bone marrow plasma cells > 60% or involved: uninvolved serum free light chain ratio >100 OR >=1 focal lesion on MRI
  • Smouldering myeloma: Paraprotein >= 30g/L OR bone marrow plasma cells 10 - 60% OR urinary monoclonal protein >= 500mg/ 24hr. 10% progress to myeloma
  • MGUS: paraprotein <= 30g/L and BM plasma cells <10%, 1% progress however size of M band related to progression risk
  • Bloods, B2 microglobulin, SPE/ IEPP/ SFLC/ urine EPG/ 24 hr urine collection for bence jones protein/ bone marrow biopsy and trephine for cytogenetics/ biopsy of tissue if suspecting amyloidosis/ skeletal survey vs MRI - bone scan no good for MM
  • Paraprotein estimation: serum/urine: IgG (70%) > IgA (20%) > IgD (5%) > LCD (5%) > N.S (2.5%) >> IgM
  • DDx paraprotein
    • most commonly myeloma related
    • haematological
      • Waldenstrom’s macroglobulinaemia (Paraprotein (IgM +/- mFLC)
      • Non Hodgkin lymphoma (rare)
      • CLL (rare)
      • Amyloid (AL)
    • non haematological
      • hepatitis C
      • Autoimmune diseases
      • Chronic infection
Staging
  • International Prognostic Index - High risk if beta 2 microglobulin > 5.5. Low risk if albumin >35, beta 2 microglobulin < 3.5
  • High risk cytogenetics include hypodiploidy, del 17p, t(4;14)
  • Low risk cytogenetics include hyperdiploidy
Management
  • As of yet there is no cure available for myeloma
  • Number of new treatments are available
  • If possible, involve patient in a clinical trial
  • MGUS/ smoldering myeloma
    • Monitor 6-12monthly for evidence of organ injury and rapidly rising paraprotein or heavy BM infiltrate
  • Skeletal protection
    • Always offer bisphosphonates
    • If lytic lesion in long bone consider prophylactic internal fixation
  • Chemotherapy
    • SCT protocol
    • Offer transplant to patient <65 (although biological age is considered now) and ECOG 0 - 2
    • Induction therapy CDT (cyclophosphomide/ Dexamethasone/ Thalidomide) or CyBORD (cyclophosphomide/ bortezemib/ dexamethasone)
    • Maintenance: steroids, thalidomide
    • Allogeneic transplant - Role is controversial, 100 day treatment related mortality is large
      •  Myeloablative allogeneic HCT is considered (usually at first relapse) in selected patients (age less than 60 to 65 years) with high risk myeloma who have a matched donor and are willing to accept a high early treatment-related mortality
      • Among patients with newly diagnosed myeloma, survival in recipients of a hematopoietic stem-cell autograft followed by a stem-cell allograft from an HLA-identical sibling is superior to that in recipients of tandem stem-cell autografts
      • 40% mortality , especially in myeloablative allografts because of immune dysfunction
    • ​Monitor disease with paraprotein/ light chain level +/- PET scan to look for disease
    • Relapse:
      • re-trial of previous chemotherapeutic agents
      • stem cell transplant if patient robust
      • Thalidomide based drugs:
        • Thalidomide - SE include constipation, somnolence, tremor, painful sensory peripheral neuropathy
        • Lenalidomide - high risk of secondary malignancy and myelodysplastic syndrome
        • Pomalidomide
      • Proteosome drugs
        • bortezemib - significant risk of Herpes Zoster reactivation therefore need to be on valacyclovir
        • carlfizomib - second generation proteosome inhibitor, evidence for prolonged progression free survival when added to lenalidomide and dexamethasone
      • Daratumumab - anti CD38 mab, CD38 uniformly expressed on multiple myeloma clonal plasma cells. Some evidence exists. 

Acute Myeloid Leukaemia

History
  • BM failure (main problem)
    • Red cells, white cells, platelets – of course can be caused by any malignancy, or non malignant disorders such as storage disorders (glycogen/ lipid storage disorders), damage from immunological attack eg aplastic anaemia, chemical agenst such as benzene can damage the stem cell and cause bone marrow failure
    • Fungal infections are quite often seen in the neutropenic setting, esp aspergills in setting of AML
    • Neutropenic mouth ulceration, aggravated by herpes simplex ulceration
  • Infiltration by leukemic cells
    • Organ infiltration by leukaemic cells can occur
    • Leukostasis – myeloid cells can go up, up to 700: eg major intracerebral complications (strokes, haemorrhage, blocks of small blood vessels), expansion f the bone marrow within the cavity = bone pain, can be very significant – rate of expansion is significant, CNS involvement esp in acute lymphoblstic leukaemia – therefore treatment would often include CNS prophylaxis (intrathecal therapy vs high dose MTX/ cytarabine), lymphadenopathy, gum hyperplasia (can ulcerate, become a major site of infection), testes (sanctuary site esp for ALL), chloromas (solid lumps of leukaemia – have green hue due to myeloperoxidase activity)
    • Metabolic effects: catabolic effects, DIC in acute leukaemias esp APML, hyperuricaemia, tumour lysis syndrome (usually in lymphoid malignancies such as burkitts lymphoma/ burkits leukaemia = 100% of cells in cell cycle because of >95% with Ki67+ --> dramatically at risk of tumour lysis, just a little bit of CTx can cause fatal tumour lysis syndrome), Hypercalcaemia is rare – more common obviously in myeloma – can get it in adult T cell lymphoma/ leukaemia related to HTLV-1, renal tubular disorders are rare, can occur in some types of acute monocytic leukaemia
Examination
  • lymphadenopathy
  • soft tissue masse of leukaemic deposit
  • gingival hypertrophy
  • anaemia and thrombocytopenia clinical signs
  • neurological examination to delineate CNS or peripheral nerve involvement
  • CCF secondary to anthracycline induced irrerversible cardiomyopathy
Investigations
  • ​FBC/ blasts/ UEC/ uric acid/ LDH/ CMP/ ECHO/ GHPS
    • need basts >20%
  • Bone marrow/ cytogenetics/ flow cytometry
  • Previously used stains e.g. myeloperoxidase – typical of acute myeloid leukaemia, and low alkaline phosphatase score
  • Cytogenetics important to determining prognosis:
    • favourable inv(16), t(15; 17), t(8, 21) = core binding factor
    • unfavourable inv(3), t(6, 9), transformed from MDS, complex karyotype - unfavourable you are more likely trying to take them to allogeneic stem cell transplantation
  • Molecular markers
    • FLT3 internal tandem dislocation- worse prognosis
    • NPM1 - better prognosis, transplant not recommended
    • CEBPA - better prognosis, transplant not recommended
Management
  • Induction followed by consolidation chemotherapy, aim for complete remission which is defined as blasts <5%
  • If at high risk of relapse then perform allograft
  • Induction
    • Modern chemotherapy for AML: 7 + 3 – cytarabine 100mg/m2 x 7 days by continuous IVI; daunorubicin 45mg/m2 x 3 days.
    • some patients require 2 doses of induction to achieve remission
    • Anthracycline = daunorubicin or idarubicin, use for 3 days
      • Topoisomerase II inhibitors
      • Main side-effect is myelosupression – onset 7 days, nadir 10 – 14, recovery 21 – 28 days
      • Myocardial toxicity --> elevated cumulative doses may lead to CHF
      • High chance of extravasation reaction [potent vesicant] --> need to get good line, only IV!
    • Cytarabine = anti-metabolite, use for 7 days
      • Myelosupression – biphasic nadir [1 – 7 days, then 15 – 24 days]
      • Drug fever is significant
      • Hepatic dysfunction – transaminitis
  • Consolidation
    • use high dose cytarabine improves survival
  • Patients for allogeneic stem cell transplant:
    • Favourable group: do no proceed to allograft
    • Adverse group: proceed to allograft
    • FLT3 mutation: proceed to allograft
  • Management of APML
    • Fusion of chromosome 15 to a bit of 17
    • Dumbell appearing cells on blood film – no platelets or neutrophils
    • Flow cytometry: large number of pro-myelocytes
    • ATRA +/- arsenic, with steroids to cover if there is a suspicion of differentiation syndrome
  • Long term management of cancer survivors
    • psychosocial care
    • each patient should receive a cancer treatment summary and follow-up care plan called a survivorship care plan
    • provide critical information regarding diagnoses, treatments, and potential late effects, as well as recommended surveillance, preventive strategies, and education and referrals for management of other medical and psychosocial needs

Acute Lymphoblastic Leukaemia

General
  • B cell ALL/precursor B lymphoblastic leukaemia - more common to have B- ALL than T- ALL
  • T cell ALL/precursor T lymphoblastic leukaemia
    • Note a typical presentation of T lymphoblastic leukaemia is a widened mediastinum, may also be lymphoma.  If pancytopenic – likely to be T-ALL
  • ALL is bimodal
    • Peak in infancy and in later adulthood
    • More common in males, unsure why
Management
  • Treatment for ALL in adults – hyperCVAD
    • Combination of cyclophosphamide, vincristine, cytarabine and dexamethasone, l-asparaginase (Complications: coagulopathy, LFT abnormalities and pancreatitis), imatinib if Ph+ (unfortunately gatekeeper mutation T315i occurs frequently with resistance to first and second generation tyrosine kinase inhibitors) , rituximab if CD20+
    • Complete remission rate 92%
    • 5 year survival: 50% in patients < 40 but down to 17% in those 60+ because of intolerance of chemotherapy
    • B Cell ALL – Blinatumomab - novel therapy with bio-engineering, such that there is the hypervariable component of IgG directed against CD3 (T cell antigen) linked to the hypervariable section of IgG recognising CD19 (B cell tumour antigen). This brings cytotoxic T cells in proximity to tumour cells, where they are programmed to release their toxic secretions --> trial evidence to suggest its use in relapsed disease
  • Goal of therapy in ALL is to debulk the number of leukaemic cells
    • Complete remission is when <5% blasts, but 80% have minimal residual disease therefore have high risk of relapse
    • after induction chemotherapy most patients undergo maintenance regime - survival benefit to decrease leukaemic bulk
      • 6 - mercaptopurine and weekly methotrexate, usually given for 2 - 3 years

Chronic Myeloid Leukaemia

General
  • Symptoms: nil (asymptomatic, seen on routine bloods) vs. splenomegaly, hypermetabolic symptoms
  • Three phases: chronic (most common phase of presentation), accelerated, blasts
    • Untreated progresses from chronic phase (3-5 years) to blast crisis
  • Diagnosis confirmed by detection of t(9;22) – Philadelphia chromosome.
    • Peripheral blood:  spectrum of myeloid cells, proliferation from the stem cell phase all through the phases of myeloid maturation.  Also get basophilia and eosinophilia. 
    • Bone marrow: hypercellular marrow - high myeloid:erythroid ratio.  Megakaryocytes are mono-lobated
    • ABL tyrosine kinase activity usually tightly regulated, with t(9; 22), BCR brought together with ABL on chromosome 9, causes constitutional activation of tyrosine kinase (transfers phosphate from ATP to another protein in signal transduction)​
Management
  • Based on tyrosine kinase inhibitors - Blocks binding site for ATP and this results in cell death via apoptosis
  • Therapy driven by response: aim for a major molecular response (MMR) - 3 log reduction in BCR-ABL transcript. Major endpoint used in most studies
  • Once imatinib started MMR achieved usually after 12 months
  • Imatinib
    • start on imatinib 400mg per day. Note that now nilotinib preferred (unless heart disease then dasatanib, unless lung disease then imatinib - eg elderly pt)
    • Monitor with FBC and peripheral blood bcr-abl each 3 months
    • Aim for molecular milestones at 3, 6 and 12 months: one log bcr-abl reduction at each timepoint
    • S/E: nausea, diarrhoea, fatigue, 15% intolerant and need to switch to second TKI
    • imatinib resistance - can be primary (10%) due to drug efflux pump, can either increase dose of imatinib to overcome barrier or change to second gen TKI as it is not dependent on this pump. Secondary resistance due to mutation in binding region of imatinib to TKI, mostly still sensitive to second gen TKI, but T315I gatekeeper mutation resistance to imatinib and all second generation TKI
    • If rising BCR-ABL in a patient
      • First think about compliance
      • Can look for mutations because
        • Some mutations give you some relative resistance which you can overcome with increased dose
        • Some mutations give you complete resistance in which case you might need to use a second generation tyrosine kinase inhibitor
      • Also type of mutation may indicate which secondary tyrosine kinase (dasatinib or nilotinib) inhibitor the patient will respond to
    • Rx with imatinib is lifelong: TWISTA study: patients in MMR for 2 years on imatinib, then stopped, 70% relapsed
  • Second generation TKIs
    • Dasatinib and nilotinib
    • Nilotinib increases cumulative incidence of MMR than imatinib irrespective of dose - ENESTnd Study 
      • SE: cardiovascular side effects, particularly at highest dose – ischaemic heart disease, peripheral vascular disease and cerebrovascular disease
      • Need to monitor lipids and if cholesterol increases, commence a statin and use cardiovascular disease targets
      • Most doctors would consider initiating aspirin
    • Dasatanib:
      • Pleural effusions especially in the elderly (usually resolve if cease dasatinib)
      • Pneumonitis
      • Pulmonary hypertension (generally reversible with cessation)
      • Bleeding
      • Use if intermediate prognostic group and CV risk factors exist
  • Allografting
    • Remains an option for patients with TKI-resistant disease or those with advanced phase e.g. late accelerated or blast crisis
    • Cure rate, at expense of co-morbidity of GVHD, in CP-CML still 80%
    • Patients with disease with many mutations don’t do more poorly with allografting 

Lymphoma

Hodgkin's lymphoma
  • Accounts for 30% of all lymphomas
  • Associated with viral aetiology – especially EBV. HIV gives mixed cellularity and highly aggressive form
  • Usually young patients (early adolescence and early adulthood) (also later peak in 4th decade of life)
  • Neoplastic tissues contain a small amount of HRS (Hodgkin-Reed Sternberg) cells (owls eye nucleus) amongst a mixture of non-neoplastic inflammatory cells.
  • 4 different histologies: nodular sclerosing (most common), lymphocyte deplete, lymphocyte predominant (good prognosis), mixed cellularity
  • Staging in accordance to Ann arbour: 
    • Single LN site (extra nodal or nodal) = Stage I
    • More than one site on same side of diaphragm = Stage II
    • Lymph nodes on both sides of diaphragm = stage III
    • Extralymphoid tissues in addition to lymphoid tissue e.g. bone or lung involvement = Stage IV
      • A = No constitutional symptoms
      • B = Fever, night sweats or loss of weight
  • Classification
    • Favourable early stage (1b-IIa)
    • Unfavourable early stage
      • (B symptoms, age >50, ESR >50, bulky and 3 + areas involved)
    • Advanced stage (III and IV)
  • Prognostication
    • Hasencleaver index
  • Treatment
    • ABVD
      • + involved field radiation
      • IV every 2 weeks for 6 months
      • SE: hairloss, neutropenia, cardiotoxicity (early or late) from Adriamycin [= donorubicin = topoisomerase inhibitor = cardiotoxicity], lung toxicity from bleomycin, vinblastine = vinca alkaloid [painful peripheral neuropathy with loss of deep tendon reflexes, SIADH
      • Low risk of infertility
    • BEACOPP escalated
      • 7 drugs
      • 3 weeks for 6 cycles
      • More toxic, more myelosuppressive, more infertility, MORE EFFECTIVE. 
    • Brentuximab Vedotin
      • Anti-CD30 monoclonal antibody combined with a cytotoxic agent (anti-tubulin agent MMAE)
      • When internalised, disrupts the microtubule network and causes apoptosis
      • Efficacy demonstrated in relapsed, refractory Hodgkin 
    • PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma
      • Nivolumab
      • Studied heavily pre-treated patients, most with the nodular sclerosing histological subtype of hodgkins lymphoma – rationale was that reed-steinberg cell expresses PDL1, and blocking this with nivolumab offers a novel mechanism – good response rates with complete remission achieved (most of these patients had relapsed after stem cell transplantations)
  • Second cancers in Hodgkin lymphoma
    • AML (2-10% at 10 years)
      • Risk factors: type of chemo (alkylateors, etoposide), age at treatment, combined modality therapy
    • NHL (1-5% at 10 years)
    • Breast cancer
      • RR up to 75 x expected (age related), related to RTx dose and field
    • Other solid tumours
      • Thyroid (x30) increase: RF radiotherapy, untreated hypothyroidism
      • Lung (x4): RF smoking, radiotherapy, dose and field size 
      • Bone/GI (x5-20): radiotherapy, field size
      • Brain (x10) unclear aetiology

Follicular Cell Lymphoma
  • Demographic and clinical features
    • t(14;18) and bcl-2 rearrangement >85%
    • Median age 60-65 at diagnosis
    • Main presentation is with disseminated disease, ~80% have disseminated disease at diagnosis (Stage III or IV)
    • Usually generalised lymphadenopathy with BM involvement +/- splenomegaly +/- hepatomegaly
    • Indolent clinical course
    • Cumulative risk of histologic transformation 25% - poor prognosis if transformation to high grade lymphoma
  • Prognositication
    • Ann arbor stage
    • FLIPI score
  • Treatment
    • Radiation therapy: Can be cured if localised disease (although localised disease is an unusual presentation)
  • Treatment: 
    • Early vs. late treatment
      • Older studies investigating chlorambucil (2003) demonstrated no significant difference/  Median overall survival 5.9 years for chlorambucil and 6.7 years for observation
      • Improves in survival over last 2 decades because of anti-CD20 therapy
      • Increased survival with stage IV due to rituxuimab (chimeric antibody – murine and human sequence)
      • Meta-analysis of studies demonstrate benefit with regards to overall survival for rituximab in follicular lymphoma
      • Ofatumumab – second generation (human antibody).  Different epitope to rituximab – may be able to be used in follicular lymphoma refractory to rituximab.
    • Chemotherapy --> must take into account co-morbidities and performance status
      • R-CHOP
      • R-CVP, FCR
      • Chlorambucil, rituximab
      • PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma
        • In this study, Idelalisib – small molecule inhibitor of PI3K-delta (B cell receptor signal transduction cascade inhibitor) was used in heavily pre-treated patients with indolent B-cell lymphoma. There was improvement in disease free survival (6% met the criterion), and side-effects were tolerable. 
    • PRIMA Study – looking at addition of maintenance therapy following induction chemotherapy: Maintenance therapy of rituximab for 2 years post induction chemotherapy resulted in improved progression free survival

DLBCL
  • Demographics and Clinical Features
    • T(14;18) and bcl-2 re-arrangements in <30%
    • Median age at diagnosis 55-60y
    • Male > Female (60:40)
    • ~50% have disseminated disease at diagnosis
      • Usually localised lymphadenopathy, BM involvement UNCOMMON +/- extranodal origin or involvement
      • Risk of CNS involvement in 5%
    • B-symptoms in 30-40%
    • Aggressive clinical course, curable in 60% of cases
  • Prognosis
    • International Prognostic Index
  • Treatment
    • R-CHOP with growth factor support
    • End of treatment PET scan highly predictive of prognosis after 6 cycles. 
      • PET negative after 6 cycles of therapy – 80% chance of cure
      • Much worse outcome if PET positive

Other lymphomas
  • Double hit lymphoma
    • Dual positivity for BCL-2 + C-MYC portends a poor prognosis, either de novo or with transformed follicular lymphoma
    • NO STANDARD TREATMENT
    • Rituximab-containing therapy provides benefit, but is still inadequate
    • Options
      • R-CHO(E)P- 14 x 6 -8 cycles
      • Burkitt protocol: BFM B-ALL or CODOX-M
    • HyperCVAD, ASCT
  • Burkitts NHL
    • Characteristic t(8;14) and c-myc
    • Highly aggressive and proliferative
    • Curable with intensive regimens
  • Primary Cerebral NHL
    • HIV related/sporadic
    • Standard therapy is high dose methotrexate and radiotherapy
  • HIV Related NHL
    • Related to CD4+ count, frequently HHV8, EBV related
    • Often extranodal, aggressive
    • Individualised treatment
  • Mantle-cell NHL
    • t(11;14) and bcl-1 translocation (cyclin D1)
    • Frequent GI involvement (lymphomatous polyposis)
    • Aggressive clinical behaviour, treatment difficult. Evidence for ibrutinib

Survivorship issues
  • Fertility
    • sperm banking
    • ovarian tissue banking
    • GnRH agonists - not proven benefits
    • embryo cryopreservation - this has the best evidence
  • Post treatment malignancy surveillance
    • secondary malignancy common
    • at least annual FBC
    • cardiac, thyroid, breast - routine annual mammogram post 10 years after mantle RTx
    • be aware of possibility of bleomycin induced pulmonary toxicity
    • psychological issues
    • dental caries
    • nutrition, exercise
    • formal survivorship plan

Other myeloproliferative disorders

Polycythaemia Rubra Vera

Natural History
  • Median survival is 20 years
  • 15 year leukaemia risk: 7%, not changed by hydroxyurea
  • 15 year myelofibrosis risk: 6%
  • 15 year thrombosis risk: 27%
History & Examination
  • Clinical features of hyperviscosity syndrome: Dizziness, tinnitus, headache, blurred vision and pruritus
  • Thrombotic disorders (erythromelagia, TIA, MI, CVA, Budd-Chiari syndrome) d/t elevated RBC mass and increased viscosity 
  • Transformation into AML, progression to myelofibrosis
  • Ruddy cyanosis, HTN, Splenomegaly, Headache, Sweating, Weight loss, Paraesthesia and dizziness
Diagnosis
  • Increased RBC mass, splenomegaly, normal PO2 and low serum EPO and Positive JAK2 mutation
  • Bone marrow: Hypercellular with increased reticulin fibrosis
  • Secondary polycythaemia if have high EPO
Management
  • Aspirin to all (Significant reduction in non-fatal arterial and venous thrombosis and cardiovascular deaths)
  • If high risk then venesect
    • >65 or history of thrombosis aiming to bring Hct < 45
    • Presence of leukocytosis is an independent risk factor for thrombosis and venesection will not address this – tend to commence them on hydroxyurea
  • Ruxolitinib (a janus kinase 1 and 2 inhibitor) : In patients with phlebotomy dependent PCV who had failed hydroxyurea cytoreductive therapy, ruxolitinib achieved the primary end point (reduction in spleen size + Hct control) significantly more than placebo N Engl J Med 2015; 372

Essential Thrombocytosis

Natural history
  • Modestly increased risk of developing MDS, AML and MF (6% at 15 years)
  • Life expectancy related to a number of thrombotic or haemorrhagic events
  • Main therapeutic goal is reduce thrombotic risk
History
  • Most are asymptomatic
  • Most common complication (and cause of death) is thrombosis
    • Not uncommon – TIA with mildly raised platelet count (e.g. 600)
  • Always think of in cases of unusual thrombosis e.g. splanchnic of cerebral veins
  • Bleeding may also occur in a smaller proportion (acquired vW disease at very high platelet counts, generally more than 1000-1200)
    • Issues in these patients using aspirin to prevent clotting but increases risk of bleeding
    • This is the group that may be given therapy to bring platelet count down
  • No linear relationship between level of platelet count and thrombotic risk
Laboratory features
  • 95% of ET patients have normal cytogenetics
  • JAK2 subgroup - Associated with higher Hb and thrombotic risk and more likely to develop PRV and myelofibrosis with time
    • JAK2 mutation in 50%
  • Calreticulin mutations described in December 2013 in 40% (JAK2 negative population) - milder disease, fewer thrombotic episodes and better survival than JAK2 patients
  • C-mpl mutations ~ 5%
Management
  • Aspirin
    • Safe, reduced thrombotic risk
    • Treatment of choice in low risk patients
  • Hydroxyurea
    • Reduces RCC, WCC and platelets and probably works by decreasing all of these
  • Anagrelide
    • Often use in patient who do not tolerate hydroxyurea (main side effect is febrile illness with rigors, 2-5% and also have LFT derangement)
    • TGA approved but not on PBS
  • Interferon
    • PBS approved
    • Response rate = 80%, intolerance = 20%
    • Drug of choice in ET patients wanting to conceive or pregnant – want normal platelet count to avoid placental infarction and miscarriage

​Myelofibrosis

  • Myelofibrosis with extramedullary haemopoiesis is a chronic myeloproliferative disorder characterised by overproduction of megakaryocytes and bone marrow stromal cells. The fibrosis causes decreased bone marrow reserve and extramedullary haematopoiesis with massive hepatosplenomegaly
  • Pathogenesis: Fibrosis of BM occurs as a result of hyperplasia of megakaryocytes. It is thought that fibroblasts are stimulated by platelet derived growth factors
  • Clinical features:
    • Signs and symptoms of anaemia
    • High or low WCC and Plt
    • Night sweats and weight loss
    • Massive hepatosplenomegaly d/t extramedullary haemopoiesis
  • Blood film: marked leukoerythroblastic findings with tear drop–shaped erythrocytes and megathrombocytes.
  • Bone marrow: aspirate is often “dry” (unsuccessful aspirate), and bone marrow biopsy shows marked fibrosis and hypercellularity
  • Treatment:
    • Cytoreduction with hydroxyurea
    • SCT for Pts <60yrs
    • Ruxolitinib – a JAK1/2 inhibitor
      • Recently published in NEJM (COMFORT-I)
      • Resulted in reduced spleen volume compared to placebo + symptomatic improvement (even without JAK 2 mutation)
      • Not yet approved on PBS

Haemophilia

Haemophilia A and Haemophilia B
  • Congenital deficiency of coagulation factor VIII = haemophilia A (1 in 5000 male births)
  • Congenital deficiency of coagulation factor IX = haemophilia B (1 in 30 000 male births)
  • X-linked recessive disorders mainly affects males whose daughters are obligate carriers of the gene defect
  • 30% are spontaneous mutations
  • Haemophilia phenotype defined by activity of factor
    • Mild (5 - 40%): Severe bleeding with major trauma or surgery
    • Moderate (1 - 5%): Occasional spontaneous bleeding and severe bleeding with major trauma or surgery
    • Severe (<1%): Spontaneous bleeding predominantly into joints and muscles
  • Bleeding manifestations of haemophilia:
    • Haemarthrosis mainly (70 - 80% - knee > elbow> ankle> shoulder). Can lead to target joints with progressive joint deformity and decreased mobility
    • Muscle/soft tissue: 10-20%
    • CNS bleeds: < 5%
  • Harm minimisation
    • Integrated care at a haemophilia centre
    • Genetic counselling
    • Education about the disease
    • Babies of known carrier mother should not be circumcised!
    • Avoid aspirin, NSAIDs.
    • Factor replacement therapy – prophylactic or in response to a bleeding episode.
    • Primary prophylaxis – aim factor levels >1%. Give factor concentrate 2- 3 x week. May need central line i.e. PICC. Prophylaxis reduces the risk of arthropathy.
    • Optimise factor levels for surgery
      • Early joint or muscle bleeding: aim factor levels of 30 - 40%. The usual haemarthrosis responds to single injection if treated early.
      • Severe muscle haematomas and undergoing dental surgery: achieve levels of 50% + Oral antifibrinolytic therapy +/- desmopressin 
      • Severe bleeding episodes such as ICH/ intra-abdominal haemorrhage or bleed to face, neck, hip require correction to 80 -100% until haemorrhage has resolved
      • Ortho surgery: initial levels of 80-100% followed in a few days by min levels of at least 30%; an exception occurs at times of wound or joint manipulation when a level of at least 50% is necessary.
      • To achieve haemostasis for major surgical procedures, an initial level of 60 - 100% is achieved. This level is followed by a prophylactic level of 30 - 50 % until wound healed, typically 10 - 14 days.
      • Half-life of recombinant human factor VIII is approximately 8 - 12 hrs. Doses are repeated on a 12-hour basis and assays are performed near the end of the 12-hour period.
  • Complications
    • Joint destruction due to haemarthroses, leading to a number of orthopaedic abnormalities. Primary prophylaxis is important. Joint destruction may need synovectomy, arthroplasty and joint replacement. 
    • Hep C, HIV (transfusions 1970 to 1985): Leading cause of death in haemophiliacs.
    • Inhibitor formation: Formation of alloantibodies to FVIII or FIX. Dx on basis of abnormal mixing study. Patients with an inhibitor and severe bleeding should be treated with recombinant human factor VIIa or FEIBA (factor eight inhibitor bypass agent).
      • To eradicate the inhibitor antibody, immune tolerance induction is performed, where a daily infusion of the missing protein is given until the inhibitor disappears, usually requiring < 1 yr.

Von-willebrand disease
  • Inherited deficiency or dysfunction in VWF
  • VWF = plasma protein that mediates initial adhesion of platelets at sites of vascular injury and binds FVIII in the circulation
  • Bleeding results due to impaired platelet adhesion or lower levels of FVIII
  • Clinical presentation
    • Bleeding: mucous membrane and skin site (bleed more like a platelet disorder than a coagulation disorder)
    • Personal history of bleeding
    • Family history of bleeding
  • Classification
    • Either patient has a quantitative or qualitative deficiency
    • Quantitative
      • Type 1: partial quantitative deficiency, mild bleeding. Rx: DDAVP, or human plasma derived VWF, antifibrinolytics
      • Type 3: complete deficiency of VWF (very rare), high bleeding risk
    • Qualitative
      • Type 2 VWF: problems with platelet adhesion and VWF

Thrombosis

History
  • History of DVT/ PEs - provoked vs unprovoked. Also look for unusual sites of thrombosis such as portal venous bed, cerebral venous sinus thrombosis
  • Miscarriages  (suggests APS)
  • Risk factors for DVT: Immobilisation, OCP, Pregnancy, Smoking, Malignancy, previous history of DVT
  • Thrombophilia screening (protein C, protein S, anti-thrombin III deficiency, factor V leiden, prothrombin gene mutation) - FHx of DVT/ PE
  • Establish any contraindications to anticoagulation
  • Ask about prior anticoagulation and adherence: INR levels, who checks, knowledge of foods and drugs to avoid whilst on warfarin
Examination
  • Establish the presence of CTEPH/ acute DVT
  • Establish the presence of post thrombotic syndrome
Investigations
  • Factor V Leiden (APC resistance): Caused by a point mutation that affects the cleavage site on the activated molecule. Heterozygotes have 8x increased VTE risk, Homozygotes have 100x risk. Heterozygotes present 4% australian population
  • Antiphospholipid antibodies: Anticardiolipin antibodies, Abs to beta2 glycoprotein: Lupus anticoagulant (prolonged APTT) - must repeat them at 12 weeks after the initial screen. Miscarriages, arterial and venous thrombosis
  • Antithrombin III deficiency
  • Protein C and S deficiency. In homozygotes of protein C deficiency, warfarin may induce skin necrosis
  • Prothrombin gene mutation
  • Plasma homocystein level
  • FBC: look for polycythemia or thrombocytosis 
  • PNH screen, JAK2, calreticulin if concerned about PNH vs myeloproliferative disorder (esp thrombosis at an unusual vascular bed)
  • Investigation for cardiac failure, nephrotic syndrome if there is clinical suspicion
Management
  • If possible, use direct acting oral anticoagulants when possible. This includes apixaban, rivaroxaban, dabigatran, edoxaban
    • Contra-indicated if GFR < 30 (<25 for apixaban), mechanical valve, cancer induced DVT (although controversial)
  • VTE provoked by a transient major risk factor: 3 months total
  • Unprovoked DVT (distal): 3 months
    • Another reasonable approach is, if risks of anticoagulation > benefits, pt asymptomatic (+ D-dimer negative), can do surveillance US in 2 weeks, and anticoagulate only if thrombus extension detection
  • Unprovoked DVT (proximal): 3 months then reconsider risk vs benefit, with aim to continue if risks of thrombosis outweigh benefits of stopping
    • in patient therapy if there is evidence of phlegmasia cerula dolens, iliofemoral DVT should have inpatient therapy
    • If anticoagulation is contraindicated or in whom the risk of bleeding is estimated to outweigh the risk of recurrent thromboembolism, insert IVC filer
    • Consider IVC filter if large proximal IVC and poor cardiopulmonary reserve
    • massive iliofemoral DVT or phlegmasia cerulea dolens with symptoms for <14 days and good functional status --> systemic or catheter-directed thrombolytic therapy, and/or clot removal (eg, catheter extraction, catheter fragmentation, surgical thrombectomy)
  • ​ elastic graduated compression stockings (GCS) should not be used for prevention of post thrombotic syndrome
  • Lifelong therapy if there is history of recurrent DVT, significant thrombophilia such as APS
  • Minimise bleeding risk
    • shortest duration possible with respect to risk benefit clinical equipoise
    • harm minimisation strategies such as falls reduction, stop unecessary drugs, review drug interactions eg CYP2D6, CYP3A4, alcohol use (note that it scores a point in the HAS-BLED risk tool)
  • Thrombophilia testing:
    • not routinely recommended, may consider if <50, recurrent, APLS Abs if arterial + venous + miscarriage Hx
  • Malignancy testing:
    • Only perform age appropriate cancer screening

History and clues
  • Sudden and unexplained fall in Hb
  • Jaundice
  • Splenomegaly
  • Gall stones at a young age
  • Associated disorders e.g. CLL
  • Family history
  • Racial origin – African or Mediterranean
  • Dark urine/shivers/shakes with intravascular haemolysis
  • Drug history
Examination
  • anaemia
  • jaundice
  • RUQ pain
  • splenomegaly
  • signs of end organ complications eg high output cardiac failure
Investigations
  • DAT (distinguish auto-immune from non-autoimmune haemolytic anaemia)
  • Hyperbilirubinaemia (unconjugated)
  • Reduced haptoglobins (not always clinically useful, other things can drop the haptoglobins.  Proteins synthesized in the liver)
  • Intravascular haemolysis: (1) raised plasma Hb (2) haemoglobinuria (3) urinary haemosiderin (4) methaemaglobinaemia
  • Raised LDH
  • Raised faecal and urinary urobilinogen 
  • Blood film:
    • spherocytes: all causes of haemolytic anaemia but major feature in hereditary spherocytocis, warm AIHA, burns, wilson's disease, phosphate deficiency
    • Fragmented and contracted cells
    • Sickle cells
    • bite cells in G6PD
  • reticulocytocis
  • PNH screen
  • osmotic fragility test
Hereditary spherocytocis
  • A/D
  • Primary defect in cytoskeleton of RBC membrane (e.g. defective spectrin and protein 4.1 interaction)
    • Production of normal RBC by BM, throughout its life it loses membrane and becomes spherocytic with osmotic fragility
  • Clinical features: Jaundice, splenomegaly, gall stones, leg ulcers, haemoytic 'crisis' triggered by EBV, aplastic crisis triggered by parvovirus B19. Usually patients are very well compensated
  • Diagnosis: Blood film, negative DAT, flow cytometry, osmotic fragility test
  • Treatment
    • Well compensated and patient asymptomatic: observation
    • More cautious these days about performing splenectomy
    • Splenectomy after appropriate vaccinations - curable
Auto-Immune Haemolytic Anaemia
  • A diagnosis of AIHA is made when there is (1) Evidence of haemolysis and (2) Evidence of auto-immunity against red cells (positive DAT)
  • Positive DAT - not necessarily haemolysis, depends on IgG subclass. Only IgG1 and IgG3 activate complement, 5% warm AIHa positive to C3d only
  • Types of AIHA
    • Cold agglutinin haemolysis < 15%
    • Warm AIHA > 85%
  • Warm AIHA caused by: (1) primary or idiopathic (2) secondary to lypmhoproliferative diseases, other malignancy, infection, connective tissue disease such as SLE, drug induced (high dose penicillin, quinine, rifampicin
  • Cold AIHA caused by IgM to I/i blood group. Only cause a problem when they fix complement at approximately 20-30 degrees Celsius. Because of (1) primary or idiopathic (2) EBV, mycoplasma infection (3) lymphoma
  • Management
    • Warm AIHA: (1) Supportive care and transfusion (may be difficult due to antibody formation from sensitised host and auto-antibody present in host reacting to a vast array of transfused cells) (2) Corticosteroids - 25% have complete response, 25% steroid response the rest partial response (3) splenectomy - not for C3d coated cells as these are only destroyed in liver (4) Rituximab - but not PBS listed (5) 
    • Cold AIHA: (1) Keep warm - can pt move to warmer environment? (2) give warmed blood (3) Rituximab has good evidence (4) often steroid refractory and not good to try splenectomy
Oxidative Haemolysis
  • Often a combination of an extracellular and intracellular cause
  • Blood film: blisters underneath membrane
  • Predisposing causes
    • G-6PD deficiency (Mediterranean type and African type): Can’t convert NADP to NADPH.  NADPH usually reduces glutathione.  If insufficient reduced glutathione you get oxidation and denaturation of the Hb 
    • Unstable haemoglobins
    • Hb H disease
  • Precipitating causes, drugs and chemicals eg naphthalene, primaquin, sulphonamides, fava beans