Leukaemia/lymphoma Flashcards
What conditions are associated with paraprotein?
Neoplastic Multiple myeloma Smouldering myeloma Monoclonal Gammopathy of Undetermined Significance (MGUS) Solitary Plasmacytoma Lymphoplasmacytic Lymphoma Non Hodgkin’s lymphoma Chronic Lymphocytic Leukaemia Primary Amyloidosis
Benign
Chronic Cold haemoglutinin disease
Transient (infection)
HIV
History and examination for heamtooncology
- Weight loss, tiredness
- Bone pain
- ‘stones, bones, abdominal moans and psychic groans’
- Considercordcompression
- Pallor,bruising,bonetenderness
- Macroglossia, neuropathy, skin lesions (amyloid)
- HyperCalcaemia • Renal failure
- Anaemia
- Bone pain
- Recurrentinfections,abnormal bleeding, amyloidosis, hyperviscosity syndrome
Investigations for heamatoncology
• FBC, U+Es, ESR, Ca • Albumin,β2M,Bloodfilm • Igs, Serum protein electrophoresis, Paraprotein • Serum free light chains • Bone marrow aspirate/trephine and myeloma FISH • ImagingMRI/PET(skeletal survey)
Differentiating MGUS/myeloma
Myeloma
clinical fetaures - Calcium ↑ Renal failure Anaemia Bone pain
paraprotein >30g/l marrow plasma cells >10%
SFLC ratio abnormal
MGUS No clinical features paraprotein <30g/l marrow plasma cells <10% Progression to symptomatic myeloma 1% a year
smouldering myeloma NO clinical features paraprotein >30g/l marrow plasma cells >10% Progression to symptomatic myeloma 10% a year
What is Multiple Myeloma?
• Neoplasticdisease
• Plasma cell accumulation in bone
marrow
• Monoclonal protein in serum and/or urine
• Related end organ damage (in symptomatic patients)
• >40 years old, Most 65-70
• More common in people of black origin
Treatment of Multiple Myeloma
Consider allograft Esp if <50 yrs
Intensive chemo <70yrs
Non-intensive Chemo >70 yrs Co-morbidities
4-6 months chemo then ASCT if under 70
4-6 months chemo
e.g Melphalan Thalidomide/lenalidomide Bortezomib dexamethasone
Plateau
Stop treatment/Consider maintenance
Relapse - ↑paraprotein
ALL Emotional support Education Management of: renal impairment Pain Infections Anaemia ↑Ca Cord compression Bisphosphonate Further chemo Another ASCT
Myeloma prognosis
- Median survival 7-10 years
* Many <50 years old now surviving >10 years • Several new treatments coming into use
Supportive Care in multiple myeloma
• Insertion of a central venous catheter
• Support for bone marrow failure
• Blood product support
• Redcellandplatelettransfusion(think ?IRRADIATED)
• Erythropoetin
• Antibiotics
• Haemostasis support
• Vit K, FFP, Cryoprecipitate
• Antiplatelet agents usually stopped
• Warfarin usually switched to LMWH
• Progesterones for premenopausal women
• Tranexamic acid
Anti emetics
Supportive care continued
• Aim to prevent as more effective than managing once symptomatic
• 5HT3 receptor antagonists (can control nausea in >60% of patients having intensive chemo), 80% if add dexamethasone
• Metoclopramide,cyclizine,prochlorperazineetccanallhavearole
• Prevention/treatment of Tumour Lysis Syndrome
• Metaboliccomplicationcausing↑uricacid,↑K,↑Cr,↑PO4,↓Ca→renalfailure
• Allopurinol, IVI mainstay of prevention
• Rasburicase,IVI,electrolyteabnormalitytreatment,dialysis
• Psychological support
• Fertility
• Menofferedspermstorage
• Women need to be counselled,
Treatment/ prevention of infection in multiple myeloma?
- G-CSF
- Mouthwashes, ‘neutropenic diet’, reverse barrier room, prophylactic abx (not usual)
- Antivirals (Aciclovir), Antifungals (- conazole), co-trimoxazole
- Fever + neutropenia = infection until proven otherwise
Specific treatment for multiple myeloma
• Reduce tumour cell burden by drugs or radiotherapy
• Several drugs acting at different parts of the cell cycle are often
used together
• Usual to give several cycles
• Wide range of drugs used to treat haem malignancies: e.g. alkylating agents, antimetabolites, anthracyclines, signal transduction inhibitors, monoclonal antibodies, vinca alkaloids, immune modulators, proteasome inhibitors, steroids
• More and more targeted drugs coming in (e.g. TKI)
What is leukaemia? what are the broad classifications
- Group of disorders characterised by accumulation of malignant white cells in blood and bone marrow
- Symptoms result from bone marrow infiltration and infiltration of organs
- Main classifications: acute vs chronic, myeloid vs lymphoid
What are the features of acute leukaemia?
• Aggressive • Malignanttransformationinstem cell or early progenitors • Resultsin: • ↑proliferation • ↓apoptosis • Cellular differentiation block • →Accumulation of blast cells and bone marrow failure • Rapidly fatal if untreated
How is acute leukaemia diagnosed?
- > 20% blast cells in bone marrow at presentation (or specific leukaemia associated cytogenetic abnormality)
- Lineage of blasts confirmed by morphology, immunophenotyping and cytogenetic/molecular analysis
Epidemiology of acute myeloid leukaemia
- Commonest in adults. Median onset 65yo.
- 10-15% of childhood leukaemias
- CGN abnormalities and response to initial treatment major prognostic indicators
Clinical features of AML
- Mainly related to BM failure due to accumulation of blasts in bone marrow
- Infections, often profound, viral, bacterial or fungal
- Bleeding/petechiae(DIC characteristic of APML)
- Gumhypertrophy,skin involvement, CNS disease
Work up for AML
History and examination
Treatment of any associated conditions e.g. infection
Blood tests: FBC and film, U+Es, LFTs, Uric acid, Calcium, LDH, Coagulation screen. Hep B/C, HIV test
Immunophenotyping
BMA +/- trephine. Cytogenetics, mutation analysis
CXR/ECG/Echo
Oocyte/sperm storage
ECOG performance status
0
Fully active
1
Restricted in strenuous activity but can do light activity/work
2
Capable of self care and ambulatory >50% of day
3
Confined to bed/chair for >50% of waking hours
4
Totally confined to bed or chair, incapable of any self care
5
Dead
Acute promyelocytic leukaemia gene
• t(15:17)
• PML gene on ch 15 is fused to retinoic
acid receptor α gene on ch 17.
• PML-RARα transcriptional repressor giving a maturation block at the promyelocyte stage
Acute promyelocytic leukaemia treatment
- Treated differently
- Up to 10% patients can die in induction/presentation due to haemorrhagic syndrome (DIC)
- FFP, platelets
- ATRA +/- arsenic or idarubicin
- May precipitate differentiation syndrome
- Prognosis excellent if survive initial presentation/induction
• General supportive therapy • Specific therapy
• Determined by age, performance status and co-morbidities of patient and prognostic factors of tumour
• Intensive chemotherapy
• Aim: induction of remission, consolidation of remission and elimination of
disease
• Intensive chemotherapy +/- stem cell transplant
• More specific therapies coming in (e.g. FLT3 inhibitors, anti CD33 monoclonal antibodies)
• Monitoring of minimal residual disease coming in • Low dose chemotherapy
• Azacitidine, low dose cytarabine, hydroxycarbamide • Supportive care only
Acute Lymphoblastic Leukaemia Pathophysiology
• Accumulation of lymphoblasts in bone marrow
• Commonest malignancy of childhood
• Peak incidence 3-7 years, secondary peak >40 years
• 85% of cases B cell lineage with equal sex incidence (Male predominence for T-ALL)
• Pathogenesis varied
• Some evidence for genetic mutations in utero/early childhood but need
second genetic hit (?abnormal response to an infection)
• Reduced incidence in those children with lots of exposure to infections • ALL cells have an average of 11 acquired genetic mutations
Acute Lymphoblastic Leukaemia clinical features
Bone marrow failure
• Anaemia, thrombocytopenia, neutropenia
• Organ infiltration
• Tender bones, lymphadenopathy, hepatosplenomegaly, meningeal
infiltration
• Testicular swelling, Mediastinal mass (T-ALL)
Acute Lymphoblastic Leukaemia investigations
- As per AML plus – look for immunoglobulin or TCR gene rearrangement
- LP (at point giving intrathecal chemotherapy anyway) • CXR – mediastinal mass T-ALL
Acute Lymphoblastic Leukaemia Treatment
• Supportive care
• Specific therapy
• Chemotherapy +/- radiotherapy
• Complex! Protocols risk adjusted to reduce treatment given to those with good prognosis
• Imatinib if Ph+ • Relapse
If soon after or during maintenance prognosis poor
-Better if years after • Toxicity
• Can be significant (AVN, cardiac SEs, impact on fertility, risk of secondary tumours
Induction
(vincristine, aspariginase, dexamethasone +/-daunorubicin)
Consolidation
?SCT
Cranial prophylaxis (intrathecal methotrexate)
Maintenance (mercaptopurine, methotrexate, vincristine, dex)
Late intensification
Maintenance (2-3 years)
Acute Lymphoblastic Leukaemia prognostic factors
Do better if low WCC, girl, child, B-ALL type, no CNS disease.
Adults
• Remission rates comparable but only 40% pfs at 5 years (90% in kids) and much lower in older adults (<5% in >70)
What is the principle of stem cell transplants
- PRINCIPLE: Eradicate a patient’s haemopoietic and immune system (and cancer if still present) by chemotherapy and/or radiotherapy. Then return stem cells from another individual or the patient’s own (if previously harvested)
- Can be allogeneic (another person), syngeneic (identical twin) or autologous (self)
- Stem cells can be collected from peripheral blood, bone marrow or umbilical cord blood
- Conditioning regimens can be myeloablative or non- myeloablative
- After 1-3 weeks of severe pancytopenia get engraftment
Indications for stem cell transplant
Allogeneic Acute leukaemias Myelodysplasia Other haem malignancies (e.g. Myeloma, lymphoma, aplastic anaemia) Thalassaemia major/sickle cell disease
Autologous Non hodgkins lymphoma Hodgkin lymphoma Multiple myeloma Primary amyloidosis
Advantages and disadvantages of Autografts
- Allows higher doses of chemo which would normally cause prolonged marrow aplasia
- Downside: tumour cells in the stem cell harvest may be re- introduced
- No GvHD.
- Mortality approx 2%
Advantages and disadvantages of Allografts
• Major morbidity and mortality
• Immunological incompatibility between donor and recipient
despite matching of the HLA.
• Can cause immunodeficiency, GvHD or graft failure and also GvL effect.
• Cause of death: Relapse, Infection, GvHD, Organ toxicity, interstitial pneumonitis
What is the pathiohysiology of Graft vs Host disease?
- Caused by donor immune cells, especially T cells reacting against recipient tissues.
- Ciclosporin and methotrexate given to prevent GvHD • Acute GvHD (1st 100 days)
- Skin, GIT and liver • Chronic GvHD
- Also affects joints, oral mucosa, AI disease etc.
Chronic myeloid leukaemia epidemiology and genetics
• Clonaldisorderofapluripotent stem cell • 15%ofleukaemias • May occur at any age but typically 40-60 • PhiladelphiaChromosome • Clinical features: weight loss, sweating, ↓Hb, bleeding, splenomegaly
Laboratory findings in Chronic myeloid leukaemia
• Leucocytosis • Basophilia Laboratory findings • Normochromic normocytic anaemia • Platelets↑↓→ • Raised uric acid • Hypercellularbonemarrowwith increase in granulocyte line • DemonstrationofPh chromosome
Treatment Chronic myeloid leukaemia
- Revolutionised by tyrosine kinase inhibitors
* Poor prognosis if accelerated phase/Acute leukaemia
Types of Chronic Leukaemias
Accumulation in blood of mature lymphocytes
B cell Chronic lymphocytic leukaemia (CLL) B- Prolymphocytic leukaemia (PLL) Hairy Cell leukaemia (HCL) Plasma cell leukaemia
T cell
Large granular leukaemia (LGL)
T-Prolymphocytic leukemia (T-PLL)
Adult T cell leukaemia/lymphoma (ATLL)
Prognosis of Chronic Leukaemias
• Generally incurable but run a chronic and fluctuating course
Chronic Lymphocytic Leukaemia epidemiology
• 60-80years,M>F2:1
• 80% of cases found incidentally
by lymphocytosis
Clinical features of Chronic Lymphocytic Leukaemia
- Lymphadenopathy
- Anaemia/thrombocytopenia
- Splenomegaly(laterstages)
- Immunosuppression–recurrent infections
- ‘B symptoms’
Staging of Chronic Lymphocytic Leukaemia
Stage (Rai) findings and survival in years
0
Lymphocytosis >5 x109 /L
>12 years
I
Above +enlarged LNs
II
As stage 0 + enlarged liver/spleen +/- LNs
III
As 0 + Hb <100g/L, +/- LNs, +/- organomegaly
IV
As 0 + Plt <100 x109 /L, +/- LNs, +/- organomegaly
<4 years
Stage (Binet) - organ enlargement and platelets A (50-60%) 0-2 areas ≥100 ≥100 B (30%) 3-5 areas C (<20%) - <100 And/or <100
Treatment of Chronic Lymphocytic Leukaemia
• For problematic lymphadenopathy/splenomegaly, constitutional symptoms or Hb or Plts <100
• Depends on age/fitness of patients
• Usually anti CD20 antibody and chemotherapy including drugs
that suppress signalling through B cell receptor
• Steroids for AIHA, ITP
• Radiotherapy for reducing size of bulky LNs if refractory to chemotherapy
• Supportive therapy: vaccinations, prophylactic anibiotics/antivirals etc, intravenous immunoglobulin
what is lymphoma and what are the two types?
- Accumulation of malignant lymphocytes in lymph nodes and other lymphoid tissue
- Hodgkin Lymphoma (HL) vs Non-Hodgkin Lymphoma (NHL) • Reed-Sternberg cell present in Hodgkin lymphoma
Epidemiology of Hodgkin lymphoma
Peak incidence young adults. Second peak in middle age
• M:F2:1
Clinical features of Hodgkin lymphoma
- Painlesslymphadenopathy (cervical>axillary>inguinal)
- Mediastinal mass
- Splenomegaly+/-hepatomegaly
- ‘B’ symptoms – Fever, itching, weight loss, sweating
Lab features of Hodgkin lymphoma
• Normochromic,normocytic anaemia, neutrophilia, eosinophilia, plts →↑↓, ESR and CRP ↑, LDH ↑
Treatment of Hodgkin lymphoma
- Supportive care (including fertility advice)
- Chemotherapy +/- radiotherapy
- Early stage
- Prognosis excellent
- Don’t want to ‘over treat’ • ABVD +/- radiotherapy
- Advanced stage • 6-8 cycles ABVD
- Relapse
- Further chemotherapy and Autograft
LAte effects of Hodgkin lymphoma
• Secondary cancers
• Myelodysplasia, AML, Non Hodgkins Lymphoma, Lung and breast
cancer
• Sterility, Intestinal Complications, coronary artery disease, lung fibrosis, neuropathy
• Reasons why we need to further risk stratify patients and give the appropriate amount of treatment to cue the disease but no more!
Non- Hodgkin Lymphoma epidemiology
• 5th Commonest malignancy in our country (17 in 100,000) • 85% B cell origin, 15% T/NK cell origin
What is the difference between Low and High Grade Lymphoma
• Low grade
• Relatively indolent, respond to chemo but unlikely to cure
• High grade
• Aggressive, rapidly fatal if untreated, respond well to chemo, more
often curable
• Aetiology in most cases unknown
• Few linked with infections
• Mutations that lead to alteration of cell cycle, failure of apoptosis etc
Non- Hodgkin Lymphoma presentation
- Painless, asymmetrical, lymphadenopathy
- B symptoms – Fever, night sweats, weight loss
- Sore throat/noisy breathing – Waldeyer’s ring involvement
- Anaemia, infections, bruising – bone marrow involvement (can also be autoimmune or due to sequestration in spleen)
- Abdominal symptoms – liver and spleen often enlarged and GIT can be involved
- Involvement of other organs – skin, brain, testis or thyroid
Non- Hodgkin Lymphoma investigations
• Bloods including FBC, film, LDH, Igs, SPE and PPL, U+Es, LFTs, Ca, Viral screen (inc. HIV)
• Lymph node biopsy
• Morphology, immunohistochemistry, genetic analysis, for B cell
lymphomas Κ or λ specificity confirms not reactive • Bone marrow biopsy
• CT/PET – staging as per HL
Non- Hodgkin Lymphoma difference In prognosis of Follicular lymphoma vs Diffuse large B cell lymphoma
• Follicular lymphoma
• Low grade lymphoma
• 25% of NHL
• Median age 60
• Median survival 10 years from diagnosis
• If grade I – Radiotherapy alone (cure), II-IV only treat if symptomatic
with combination chemotherapy then maintenance rituximab
• Diffuse large B cell lymphoma
• High grade lymphoma
• Serious if left untreated.
• R-CHOP +/- MTX if high risk disease to prevent CNS disease • Overall long term survival 65%
Myeloproliferative disorders genetics
- Clonal stem cell disorders causing proliferation of one or more of the haemopoetic lineages
- Polycythaemiavera(PV), Essential thrombocythaemia (ET), Primary Myelofibrosis (PMF)
- Acquired mutations of the genes that encode tyrosine kinase proteins (JAK2, MPL, CALR)
- JAK2 mutation rate: 97% PV, 50- 60% ET and PMF
- CALR mutation rate: 30% of ET and PMF
What is polycythemia?
Absolute increase in RBC mass
History and examination for polycythemia
• Occasional headaches, No blurred vision, No itching, No red flag symptoms. Not a gym goer
• No FH of polycythaemia
• No medications including no anabolic steroid/epo use. Minimal
ETOH. Non smoker
• Mild splenomegaly, plethoric. Nil else. Not overweight
• Repeat sample
Investigation sofr polycythemia
- Stage 1
- FBC/film, JAK2 mutation, Ferritin, Renal and LFTs
- Stage 2
- RCM, arterial O2 sats, Abdominal USS, Epo, BMA +T and CGN,
- Stage 3
- Arterial O2 dissociation, Sleep study, Lung function tests, Gene mutations (EPOR, VHL, EGLN1/PHD2)
What are the clinical features of polycythemia vera
- Usually disease of older people. Equal sex incidence
- Clinical features from hyperviscosity, hypervolaemia, hypermetabolism or thrombosis.
- Headaches, SOB, blurred vision, night sweats • Itching esp after hot bath
- Plethoric appearance, conjunctival suffusion • Splenomegaly (75% of patients)
- Haemorrhage or thrombosis • Gout
Treatment of polycythemia vera
- Aims;
- Decrease thrombotic and haemorrhagic risk • Manage symptoms
- Decrease risk of transformation to MF/AML
- Treatment
- Venesection (to keep HCT <0.45)
- Cytoreductive therapy
- Aspirin for all and aggressive management of other thrombotic risk factors
- JAK2 inhibitors
Pathophysiology of Essential Thrombocytosis
- Megakaryocyte proliferation leading to a sustained increase in platelet production and platelets >450 x 109/L
- No BCR-ABL rearrangement, no bone marrow fibrosis, no reactive cause of thrombocytosis
- JAK2 mutation 50-60%, CALR 30%, MPL 5%
Essential Thrombocytosis clinical features
- Thrombosis (arterial or venous) and haemorrhage (acute or chronic)
- Erythromelalgia–burning symptom in hands or feet relieved by aspirin
- Splenomegaly (40%). Can infarct spleen and then have splenic atrophy
Essential Thrombocytosis Treatment
- Reduce risk of thrombosis or haemorrhage
- Aggressively manage other cardiovascular risk factors
- Smoking, hypercholestrolaemia, diabetes, obesity etc
- low dose aspirin
- If high risk (>60y.o, platelets >1500 x 109/L, previous thrombosis/haemorrhage) cytoreductive therapy
- If low risk (<40 y.o. no high risk features) aspirin only
- Medium risk group ?
- Prognosis good – often well controlled for 10-20 years. V. small risk of transformation to AML. 10-20% transform to myelofibrosis
Myelofibrosis epidemiology and clinical features
- Fibrosis of the bone marrow together with development of haemopoesis in liver and spleen
- Usually older people
- Anaemia and massive splenomegaly typical
- Symptoms from massive splenomegaly (early satiety, pain, indigestion)
- Weight loss, night sweats, fever common
- 1/3 of patients will have PMH of PV or ET
- JAK2 mutation in 55%, CALR 25%, MPL 10% of patients
Laboratory findings in Myelofibrosis
- Normochromic, normocytic anaemia
- White cell count and platelet count usually high at presentation (then fall)
- Leucoerythroblastic blood film and tear drop red cells
- Bone marrow trephine fibrotic and hypercellular, increased megas
- Mutations assoc with MPN
- Highurate,LDH
Myelofibrosis treatment
• Aim: reduce effects of anaemia and splenomegaly
• Blood transfusions and folic acid • JAK2inhibitors,
hydroxycarbamide, other agents
• Splenectomy/splenic radiotherapy
• Median survival 5 years
• SCTcurativeforsomepatients • Approx 30% transform to AML
What is Myelodysplasia
• Clonal disorders of stem cells characterised by increasing bone marrow failure with dysplastic changes in 1 or more haemopoetic cell lineages
• Hypercellular bone marrow but cytopenias in blood (ineffective haemopoesis)
• Pathogenesis unclear – genetic change in pluripotent stem cell. ?role of immune system
• Often progresses to AML
• May be primary (de-novo) or secondary to
chemotherapy/radiotherapy (therapy related MDS)
• Incidence 4 in 100,000. M>F, >50% of patients >70y.o
Clincial features of Myelodysplasia
- Often insidious onset
- Sx, if present of bone marrow failiure
- Anaemia, infections, bruising/bleeding
- Spleen normal size
- Need to rule out other causes of dysplasia (alcohol, megaloblastic anaemia, recovery from chemotherapy etc)
Myelodysplasia treatment
• Low risk MDS • <5% blasts, 1 cytopenia, favourable cytogenetics • Options: • Activeobservation • Growthfactors(G-CSF,epo) • Transfusion • Antibiotics • Consider iron chelation after 20- 50 units red cells or ferritin >1000 • SCT chance of cure in selected patients • High risk MDS • Intensive chemotherapy • Stem cell transplant • Azacitidine • Supportivecare • Transfusion • antibiotics
