Haematology: Myeloma and Lymphoma

• Basics: Understanding Blood Cancers
• Acute leukaemia: Acute Myeloid Leukaemia | Acute Promyelocytic Leukaemia | Acute Lymphoblastic Leukaemia
• Chronic leukaemia: Chronic Myeloid Leukaemia | Chronic Lymphocytic Leukaemia | Other Leukaemias and Mastocytosis
• Marrow neoplasms: Polycythaemia Vera | Essential Thrombocythaemia | Myelofibrosis | Myelodysplastic Syndromes
• Treatment and support: Stem Cell Transplant and CAR-T | Supportive Care in Blood Cancers
• Revision: Drug Reference Table | Spot the Diagnosis | Exam-style Scenarios | Key Points | Guidelines and Further Reading

🧪 Leukaemias, myeloproliferative neoplasms and myelodysplasia are cancers of the bone marrow. They range from conditions people live with for decades (CLL, essential thrombocythaemia) to emergencies that kill within days without treatment (acute promyelocytic leukaemia). Targeted drugs have transformed several of them - CML is now often a near-normal-life-expectancy condition. Lymphoma and myeloma have their own chapter.
Your four questions for every patient: Is this acute (blasts, rapidly falling counts) or chronic? Is there an emergency - DIC, leukostasis, tumour lysis, neutropenic sepsis? What do the molecular and genetic tests show, since they now decide treatment? Is the patient fit for intensive treatment, and what matters to them?

Understanding Blood Cancers

• Myeloid vs lymphoid:
  • Myeloid cancers arise from cells that make red cells, platelets, neutrophils and monocytes - AML, CML, MPNs, MDS.
  • Lymphoid cancers arise from B or T lymphocytes - ALL, CLL, lymphomas, myeloma.
• Acute vs chronic:
  • Acute leukaemias have immature blasts that crowd out the marrow - rapid onset, life-threatening.
  • Chronic leukaemias have mature-looking cells that accumulate slowly.
• Diagnosis (WHO 2022 classification) uses:
  • Blood film.
  • Bone marrow aspirate and trephine.
  • Flow cytometry (immunophenotype).
  • Cytogenetics and molecular genetics - these now define many diseases and guide treatment.
• When to refer urgently (NICE NG12):
  • Same-day haematology for a blood film suggesting acute leukaemia, or in children and young people with unexplained petechiae or hepatosplenomegaly.
  • Very urgent FBC (within 48 hours) for unexplained pallor, fatigue, fever, persistent infections, lymphadenopathy, bone pain, bruising or bleeding.

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Acute Myeloid Leukaemia

What it is: Rapidly growing immature myeloid cells (myeloblasts) fill the marrow. It is the commonest acute leukaemia in adults (median age about 70).

Risk factors:

• Older age.
• Previous MDS or MPN.
• Previous chemotherapy or radiotherapy ("therapy-related").
• Smoking; benzene.
• Down syndrome; Fanconi anaemia.

Features - mostly from marrow failure, developing over weeks:

• Anaemia - tiredness, breathlessness.
• Infections - neutropenia.
• Bleeding and bruising - low platelets, DIC.
• Gum swelling and skin lumps (monocytic types).
• Leukostasis (very high white count) - breathlessness, hypoxia, confusion, visual changes.

Diagnosis:

• FBC - often high or low white cells, low Hb and platelets.
• Film - blasts, sometimes with Auer rods.
• Bone marrow - 20% or more blasts (lower if certain genetic changes are present).
• Cytogenetics and molecular tests - e.g. FLT3, NPM1, core binding factor translocations, TP53 - define risk (ELN categories).
• Clotting screen (DIC), LDH, urate, U&E (tumour lysis).

Treatment:

• Fit patients - intensive chemotherapy:
  • Induction ("7+3" - cytarabine with daunorubicin), plus targeted drugs (e.g. midostaurin for FLT3-mutated AML, gemtuzumab ozogamicin for some favourable types).
  • Consolidation chemotherapy.
  • Allogeneic stem cell transplant for intermediate- and high-risk disease in first remission.
• Less fit or older patients:
  • Azacitidine with venetoclax (lower-intensity treatment with good responses).
  • Low-dose cytarabine.
  • Or best supportive care.
• Supportive care: Tumour lysis prevention, transfusions, antimicrobial prophylaxis (including antifungals), and rapid treatment of neutropenic fever.
• Outlook: About 40–50% of younger adults are cured. Outcomes in older people are poorer.

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Acute Promyelocytic Leukaemia

• What it is: A subtype of AML with the t(15;17) translocation (PML–RARA). Abnormal promyelocytes release substances that cause severe DIC.
• Who: Often younger adults.
• Features:
  • Bleeding - bruising, gum bleeding, heavy periods, intracranial haemorrhage.
  • DIC - low platelets, low fibrinogen, prolonged PT.
  • Often a low white count.
  • Film - abnormal promyelocytes, many Auer rods ("faggot cells").
• A medical emergency - early death from bleeding is the main risk.
  • Start ATRA (all-trans retinoic acid) immediately on suspicion - don't wait for genetic confirmation.
  • Aggressive blood product support - platelets over 30–50, fibrinogen over 1.5 g/L (cryoprecipitate), FFP.
  • Avoid invasive procedures (lumbar puncture, central lines) where possible until coagulopathy is corrected.
• Treatment: ATRA plus arsenic trioxide (chemotherapy-free for low and intermediate risk); chemotherapy added for high-risk disease.
• Differentiation syndrome (from ATRA or arsenic):
  • Fever, breathlessness, pulmonary infiltrates, pleural and pericardial effusions, weight gain, kidney injury.
  • Treat with dexamethasone.
• Arsenic prolongs the QT interval - check ECG, potassium and magnesium.
• Outlook: Over 90% are cured if they survive the first weeks.

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Acute Lymphoblastic Leukaemia

• Who:
  • The commonest childhood cancer (peak age 2–5).
  • A second peak in older adults.
  • Higher risk in Down syndrome.
• Features:
  • Marrow failure (pallor, infections, bruising).
  • Bone pain (children may limp or refuse to walk).
  • Lymphadenopathy; hepatosplenomegaly.
  • T-cell ALL - mediastinal mass (risk of SVC obstruction and airway compression).
  • CNS involvement (headache, cranial nerve palsies).
  • Testicular involvement.
• Diagnosis: Blasts on film and marrow; flow cytometry (B or T); genetics - Philadelphia chromosome (BCR–ABL1) is common in adults.
• Treatment - long, multi-phase chemotherapy (about 2–3 years):
  • Induction, consolidation, interim maintenance, delayed intensification, maintenance.
  • CNS-directed therapy (intrathecal chemotherapy).
  • Tyrosine kinase inhibitors (e.g. imatinib, ponatinib) for Philadelphia-positive ALL.
  • Immunotherapy - blinatumomab, inotuzumab ozogamicin, CAR-T cells for relapsed or residual disease.
  • Measurable residual disease (MRD) testing guides intensity and transplant decisions.
  • Allogeneic transplant for high-risk adults.
• Outlook: About 90% of children are cured; around 40–50% of adults (better with newer treatments).
• Late effects in childhood survivors - heart (anthracyclines), fertility, growth, learning, second cancers; long-term follow-up.

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Chronic Myeloid Leukaemia

What it is: A myeloproliferative neoplasm driven by the Philadelphia chromosome - t(9;22), producing the BCR–ABL1 tyrosine kinase. Usually diagnosed in middle age.

Features (often found by chance on a blood count):

• Fatigue, weight loss, sweats.
• Massive splenomegaly (left upper quadrant discomfort, early fullness).
• Very high white count with the full range of myeloid cells (myelocytes, metamyelocytes) and raised basophils.
• Raised platelets; anaemia.
• Rarely leukostasis or gout.

Phases:

• Chronic phase (most at diagnosis).
• Accelerated and blast phase (behaves like acute leukaemia) - now uncommon with treatment.

Diagnosis: BCR–ABL1 by PCR (blood); cytogenetics; bone marrow.

Treatment - tyrosine kinase inhibitors (TKIs) (tablets, usually long-term):

• Imatinib - fluid retention, muscle cramps, nausea.
• Dasatinib - pleural effusions, pulmonary hypertension.
• Nilotinib - vascular events, QT prolongation, high glucose and lipids, pancreatitis.
• Bosutinib - diarrhoea, liver toxicity.
• Asciminib and ponatinib (for resistance, including the T315I mutation).

Monitoring: BCR–ABL1 PCR every 3 months - aim for a major molecular response.

Treatment-free remission: After several years of a deep, stable response, about half can stop TKIs with close monitoring.

Outlook: Near-normal life expectancy for most.

Practical points:

• Check drug interactions (many TKIs are CYP3A4-metabolised).
• TKIs are teratogenic - pregnancy needs specialist planning.
• Adherence is crucial.

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Chronic Lymphocytic Leukaemia

What it is: An accumulation of mature-looking B lymphocytes. It is the commonest leukaemia in the UK, mostly in older people (median age about 70).

Diagnosis:

• B-cell lymphocytosis over 5 × 10⁹/L for at least 3 months.
• Smear cells on the film.
• Flow cytometry - CD5, CD19, CD23 positive.
• Monoclonal B-cell lymphocytosis (MBL) - a smaller clone (under 5 × 10⁹/L) without symptoms; a small yearly risk of CLL.

Staging: Binet (A, B, C) by the number of lymph node areas and the presence of anaemia or low platelets.

Features:

• Often no symptoms (found on routine FBC).
• Painless lymphadenopathy; splenomegaly.
• B symptoms - fever, night sweats, weight loss.
• Recurrent infections (low immunoglobulins).

Complications:

• Infections - chest infections, shingles.
• Autoimmune cytopenias - warm AIHA, ITP.
• Richter's transformation - change to aggressive lymphoma: rapidly enlarging nodes, B symptoms, very high LDH. Poor prognosis.
• Second cancers, especially skin (sun protection, skin checks).

Management:

• "Watch and wait" for early, stable, symptom-free disease - early treatment doesn't improve survival.
• Treat active disease:
  • Bone marrow failure.
  • Bulky or symptomatic nodes or spleen.
  • Rapid lymphocyte doubling.
  • B symptoms.
  • Autoimmune cytopenias not responding to steroids.
• Test for TP53 mutation and 17p deletion before treatment - these respond poorly to chemotherapy.
• Treatment options (mostly chemotherapy-free now):
  • BTK inhibitors - ibrutinib, acalabrutinib, zanubrutinib - continuous tablets. Side effects: AF, bleeding (caution with anticoagulants), hypertension, infections.
  • Venetoclax with obinutuzumab (fixed duration). Venetoclax carries a high tumour lysis syndrome risk - a slow dose ramp-up with hydration and monitoring.
  • Venetoclax with ibrutinib (fixed duration).
• Supportive care:
  • Vaccinations - pneumococcal, influenza, COVID-19, Shingrix. No live vaccines.
  • Immunoglobulin replacement for recurrent serious infections with low IgG.
  • Irradiated blood if treated with purine analogues or bendamustine.

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Other Leukaemias and Mastocytosis

• Hairy cell leukaemia:
  • Middle-aged men.
  • Pancytopenia with monocytopenia; splenomegaly without lymphadenopathy.
  • "Hairy" B cells on the film; "dry tap" on marrow.
  • BRAF V600E mutation.
  • Cladribine - highly effective.
• Chronic myelomonocytic leukaemia (CMML): Persistent monocytosis with dysplasia; MDS and MPN overlap; older people. Hydroxycarbamide, azacitidine, transplant.
• Large granular lymphocytic leukaemia: Neutropenia, recurrent infections, rheumatoid arthritis association, pure red cell aplasia. Methotrexate.
• Adult T-cell leukaemia/lymphoma - HTLV-1 (Caribbean, Japan); hypercalcaemia, skin lesions.
• Systemic mastocytosis:
  • Clonal mast cells (KIT D816V mutation).
  • Flushing, itching, anaphylaxis (especially to insect stings), diarrhoea, osteoporosis.
  • Skin lesions - urticaria pigmentosa (Darier's sign - they swell when rubbed).
  • Raised serum tryptase.
  • Treatment: Antihistamines, mast cell stabilisers, adrenaline pens; midostaurin or avapritinib for advanced disease.

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Polycythaemia Vera

What it is: A myeloproliferative neoplasm (MPN) with too many red cells, often with raised white cells and platelets. Over 95% have the JAK2 V617F mutation (the rest have JAK2 exon 12).

Features:

• Headache, dizziness, visual disturbance; plethora (red face).
• Itching after a hot bath (aquagenic pruritus).
• Erythromelalgia - burning red hands and feet (responds to aspirin).
• Thrombosis - arterial and venous, including unusual sites (Budd–Chiari, portal vein).
• Splenomegaly; gout.
• Often found on a routine FBC.

Diagnosis:

• Raised Hb or haematocrit.
• JAK2 mutation.
• Low serum EPO.
• Bone marrow in some.
• Exclude secondary causes (see the Red Cells chapter).

Treatment:

• Venesection to keep the haematocrit under 0.45 (the key target - reduces thrombosis).
• Low-dose aspirin (75 mg daily) unless contraindicated.
• Manage cardiovascular risk - stop smoking; treat BP, lipids, diabetes.
• Cytoreduction for high-risk patients (age over 60 or previous thrombosis), or poor tolerance of venesection, or symptomatic splenomegaly:
  • Hydroxycarbamide.
  • Interferon (ropeginterferon alfa-2b - preferred in younger people and pregnancy).
  • Ruxolitinib if resistant or intolerant.
• Long-term risks: Transformation to myelofibrosis or AML (low, slow).

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Essential Thrombocythaemia

• What it is: An MPN with a persistently raised platelet count (over 450 × 10⁹/L).
• Driver mutations: JAK2 (about 55%), CALR (about 25%), MPL; some are "triple negative".
• First exclude reactive thrombocytosis - much commoner:
  • Iron deficiency.
  • Infection and inflammation.
  • Cancer.
  • After splenectomy.
  • Bleeding; surgery.
• Features:
  • Often no symptoms.
  • Thrombosis (arterial more than venous); erythromelalgia; headache; visual symptoms.
  • Bleeding - at very high counts (over about 1,000–1,500), from acquired VWD.
  • Miscarriage.
• Treatment - based on thrombosis risk:
  • Low risk (under 60, no thrombosis, JAK2 negative) - aspirin or observation; cardiovascular risk management.
  • High risk (over 60, or previous thrombosis, or platelets over 1,500) - aspirin plus cytoreduction: hydroxycarbamide, anagrelide, or interferon (younger people, pregnancy).
  • Avoid aspirin if acquired VWD is causing bleeding.
• Outlook: Near-normal life expectancy; small risk of transformation to myelofibrosis or AML.

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Myelofibrosis

• What it is: An MPN in which the marrow becomes scarred (fibrotic). Blood cells are then made in the spleen and liver (extramedullary haematopoiesis).
  • Primary, or following PV or ET.
  • JAK2, CALR or MPL mutations.
• Features:
  • Massive splenomegaly (abdominal discomfort, early fullness).
  • Constitutional symptoms - fatigue, night sweats, fever, weight loss, itch.
  • Anaemia; cytopenias.
  • Bone pain; portal hypertension.
• Blood film: Teardrop cells (dacrocytes) and a leukoerythroblastic picture.
• Bone marrow: "Dry tap" on aspiration; trephine shows fibrosis.
• Risk scoring (DIPSS) guides treatment.
• Treatment:
  • JAK inhibitors - ruxolitinib (reduces spleen and symptoms; worsens anaemia and low platelets; infections such as shingles), fedratinib, momelotinib (helps anaemia), pacritinib (low platelets).
  • Anaemia - transfusion, ESAs, danazol.
  • Allogeneic stem cell transplant - the only cure; for fitter, higher-risk patients.
  • Splenic radiotherapy or splenectomy (rare).
• Outlook: Variable - median survival several years; transformation to AML in about 10–20%.

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Myelodysplastic Syndromes

What it is: A group of marrow cancers in which the marrow produces abnormal (dysplastic) cells that don't work and die early. This causes cytopenias despite a full marrow. It is mainly a disease of older people (median about 75) and can progress to AML.

Risk factors:

• Age.
• Previous chemotherapy or radiotherapy.
• Smoking; benzene.
• Inherited marrow failure syndromes.

Features:

• Anaemia (often macrocytic) - tiredness, breathlessness.
• Infections.
• Bruising.
• Often found on FBC in an older person with unexplained macrocytic anaemia.

Diagnosis:

• FBC and film - dysplasia (e.g. hypogranular neutrophils, abnormal nuclei).
• Bone marrow - dysplasia, blast percentage, ring sideroblasts.
• Cytogenetics and molecular tests (e.g. del(5q), SF3B1, TP53).
• Exclude B12, folate, copper, alcohol, drugs, HIV.

Risk: IPSS-R / IPSS-M scores - lower risk vs higher risk.

Treatment:

• Lower risk - aim to improve blood counts and quality of life:
  • Transfusion support; iron chelation if heavily transfused with a good outlook.
  • Erythropoiesis-stimulating agents (if EPO is low).
  • Luspatercept (especially with ring sideroblasts or SF3B1 mutation).
  • Lenalidomide for del(5q) MDS.
• Higher risk:
  • Azacitidine (hypomethylating agent).
  • Allogeneic stem cell transplant - the only cure, for fit patients.
• Related terms:
  • Clonal haematopoiesis of indeterminate potential (CHIP) - blood cancer mutations in people with normal counts. Common with age; a small risk of blood cancer and higher cardiovascular risk.
  • CCUS - clonal cytopenia of undetermined significance.

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Stem Cell Transplant and CAR-T

• Autologous transplant (patient's own stem cells):
  • Allows very high-dose chemotherapy ("rescue").
  • Used in myeloma and relapsed lymphoma.
  • Lower risk (no graft-versus-host disease).
• Allogeneic transplant (donor stem cells - sibling, unrelated or haploidentical):
  • The donor immune system attacks the cancer (graft-versus-leukaemia effect).
  • Used in AML, ALL, MDS, myelofibrosis, aplastic anaemia, some inherited disorders.
  • Higher risk - treatment-related mortality of about 10–20%.
• Complications of allogeneic transplant:
  • Infections - bacterial (neutropenic phase), CMV reactivation (monitored by PCR), fungal (Aspergillus), PCP, EBV (post-transplant lymphoproliferative disorder).
  • Acute graft-versus-host disease (usually in the first 100 days) - skin rash (palms and soles), diarrhoea, jaundice. Treated with steroids, ruxolitinib.
  • Chronic GvHD - dry eyes and mouth, skin thickening (scleroderma-like), mouth ulcers, lung disease (bronchiolitis obliterans), joint stiffness.
  • Sinusoidal obstruction syndrome (VOD) - painful liver, weight gain, jaundice.
  • Graft failure; relapse.
  • Late effects - infertility, early menopause, cataracts, osteoporosis, cardiovascular disease, second cancers, endocrine problems.
• After transplant:
  • Irradiated blood.
  • Revaccination (all childhood vaccines again).
  • Long-term specialist follow-up.
• CAR-T cell therapy - the patient's own T cells are engineered to attack the cancer (e.g. CD19 in lymphoma and ALL; BCMA in myeloma):
  • Cytokine release syndrome - fever, low BP, hypoxia. Treated with tocilizumab and steroids.
  • ICANS (neurotoxicity) - confusion, aphasia, seizures, cerebral oedema. Treated with steroids.
  • Prolonged cytopenias; low immunoglobulins; infections.
  • Patients must stay near the treatment centre and not drive for 8 weeks.

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Supportive Care in Blood Cancers

• Neutropenic fever: An emergency - IV antibiotics within 1 hour (see the Oncological Emergencies chapter).
• Antimicrobial prophylaxis (depending on treatment):
  • Antibacterial - e.g. levofloxacin during profound neutropenia.
  • Antifungal - e.g. posaconazole in AML induction (interacts with venetoclax and others).
  • Antiviral - aciclovir.
  • PCP - co-trimoxazole.
  • Hepatitis B prophylaxis if HBsAg or anti-HBc positive (especially with rituximab).
• Growth factors: G-CSF (filgrastim) shortens neutropenia after some chemotherapy.
• Transfusion: Restrictive thresholds; prophylactic platelets under 10 × 10⁹/L; irradiated products where needed.
• Tumour lysis prevention: Hydration, allopurinol, or rasburicase for high risk (check G6PD first).
• Central venous access (PICC or tunnelled lines) - infection and thrombosis risks.
• Fertility preservation before treatment (sperm or egg storage) where possible.
• Mouth care and nutrition; psychological support.
• Palliative care alongside active treatment where appropriate; many older patients choose less intensive approaches.

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Drug Reference Table

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Spot the Diagnosis

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Exam-style Scenarios

1. A 32-year-old woman has bruising and gum bleeding. Platelets 22, fibrinogen 0.8 g/L, PT prolonged. The film shows abnormal promyelocytes.
Answer: Suspected APL with DIC - emergency.

• Start ATRA immediately; same-day haematology.
• Cryoprecipitate (fibrinogen over 1.5), platelets (over 30–50), FFP.
• Confirm PML–RARA; then ATRA plus arsenic trioxide; watch for differentiation syndrome.

2. A 74-year-old has a lymphocyte count of 18 × 10⁹/L on routine bloods. Hb and platelets are normal; there are small nodes in the neck.
Answer: CLL (Binet A).

• Flow cytometry to confirm.
• Watch and wait; vaccinations (no live vaccines).
• Advise on infection, skin checks and warning symptoms; treat if disease becomes active.

3. A 55-year-old has a WCC of 140 × 10⁹/L with basophilia and a spleen palpable to the umbilicus.
Answer: Chronic myeloid leukaemia.

• BCR–ABL PCR and bone marrow.
• Start a TKI (e.g. imatinib); allopurinol initially.
• BCR–ABL monitoring every 3 months; check interactions.

4. A 66-year-old has a haematocrit of 0.58, itch after showers and a previous TIA. JAK2 is positive.
Answer: High-risk polycythaemia vera.

• Venesection to haematocrit under 0.45; aspirin.
• Cytoreduction (hydroxycarbamide); manage vascular risk factors.

5. An 82-year-old has transfusion-dependent anaemia. Marrow shows MDS with ring sideroblasts and an SF3B1 mutation, lower risk.
Answer: Lower-risk MDS.

• Transfusion support; consider ESA (if EPO is low) or luspatercept.
• Iron chelation if long-term transfusion and a good outlook.
• Discuss goals of care.

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Key Points

• Blasts on a blood film need same-day haematology review.
• AML presents with marrow failure. Fit patients get intensive chemotherapy and transplant; unfit patients get azacitidine and venetoclax.
• APL: DIC and bleeding - start ATRA on suspicion; replace fibrinogen and platelets; over 90% cure.
• ALL: the commonest childhood cancer; mediastinal mass in T-ALL; about 90% of children cured.
• CML: Philadelphia chromosome (BCR–ABL1); high WCC with basophils and massive spleen; TKIs give near-normal survival.
• CLL: often watch and wait; complications include infections, AIHA, ITP and Richter's transformation.
• Test for TP53 and 17p deletion before treating CLL; BTK inhibitors cause AF and bleeding; venetoclax needs TLS precautions.
• PV: JAK2, venesection to haematocrit under 0.45, aspirin, cytoreduction if high risk.
• ET: exclude reactive causes first (iron deficiency, inflammation, cancer).
• Myelofibrosis: teardrop cells, dry tap, massive spleen - JAK inhibitors; transplant is the only cure.
• MDS: older people with macrocytic anaemia and cytopenias; risk scores guide treatment.
• Allogeneic transplant: watch for infection, GvHD and VOD. CAR-T: cytokine release syndrome and ICANS.
• Prophylaxis against bacteria, fungi, viruses, PCP and hepatitis B reactivation as indicated.

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Guidelines and Further Reading

• NICE NG47: Haematological cancers - improving outcomes
• NICE NG12: Suspected cancer - recognition and referral
• WHO Classification of Haematolymphoid Tumours (5th edition, 2022); ELN 2022 AML recommendations
• BSH guidelines: CLL; CML; polycythaemia vera; essential thrombocythaemia; myelofibrosis; MDS
• NICE technology appraisals for individual leukaemia, MPN and MDS drugs
• Blood Cancer UK; Leukaemia Care
• BNF - for current doses

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