Haematology for Doctors

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The RATIFY Trial: Midostaurin in FLT3-Mutated AML
Have you ever wondered why we give patients with FLT3 mutated AML midostaurin during their induction and consolidation chemotherapy? Today we will be talking about the RATIFY trial to find out.

The RATIFY trial (CALGB 10603) was a pivotal phase III, randomized, double-blind, placebo-controlled study that evaluated the efficacy of adding midostaurin, a multikinase FLT3 inhibitor, to standard chemotherapy in adults aged 18–59 with newly diagnosed FLT3-mutated acute myeloid leukemia (AML). The trial enrolled 717 patients across 225 sites in 17 countries.

Study Design
- Population: Patients aged 18–59 with newly diagnosed AML harboring FLT3 mutations (including both internal tandem duplication [ITD] and tyrosine kinase domain [TKD] mutations).
- Intervention: All patients received standard induction chemotherapy (daunorubicin and cytarabine). Those achieving remission proceeded to consolidation therapy. Patients were randomized to receive either midostaurin (50 mg twice daily) or placebo, administered during induction, consolidation, and as maintenance therapy for up to 12 months.
Key Outcomes
- Overall Survival (OS): The addition of midostaurin significantly improved OS. The median OS was 74.7 monthsin the midostaurin group compared to 25.6 months in the placebo group. The hazard ratio (HR) for death was 0.78(one-sided p = 0.009), indicating a 22% reduction in the risk of death.
- Event-Free Survival (EFS): Midostaurin also improved EFS, with a median of 8.2 months versus 3.0 months in the placebo group (HR = 0.79; p = 0.0067).
https://www.nejm.org/doi/full/10.1056/NEJMoa1614359

Long-Term Follow-Up

A 10-year follow-up analysis confirmed the durability of midostaurin’s benefit:
- OS Benefit: The survival advantage persisted over a decade, with a sustained improvement in OS for patients receiving midostaurin.
- EFS Benefit: The improvement in EFS was maintained, reinforcing the long-term efficacy of midostaurin in combination with chemotherapy.
Subgroup Analyses

Midostaurin’s benefit was observed across various FLT3 mutation subtypes:
- FLT3-ITD: Patients with both high and low allelic ratios of FLT3-ITD mutations experienced improved outcomes.
- FLT3-TKD: Patients with TKD mutations also benefited from midostaurin addition.
Limitations
- Age Restriction: The trial included only patients aged 18–59, limiting the generalizability of results to older populations.
- Maintenance Therapy: The study included a maintenance phase with midostaurin, but the specific contribution of maintenance therapy to overall outcomes remains unclear.
- Toxicity: While midostaurin was generally well-tolerated, grade 3 infections occurred in 52% of patients in the midostaurin group, comparable to the placebo group.
In summary, the RATIFY trial established the addition of midostaurin to standard chemotherapy as a new standard of care for younger adults with FLT3-mutated AML, demonstrating significant improvements in survival outcomes. However, considerations regarding its applicability to older patients and the role of maintenance therapy warrant further investigation.
April 19, 2025
A brief introduction to Hodgkin Lymphoma
Hodgkin Lymphoma (HL) is a malignant lymphoma characterised by the presence of Reed-Sternberg cells within an inflammatory background. It is an important and potentially curable haematological malignancy, especially in younger patients.

Epidemiology
- Bimodal age distribution: Peaks in young adults (15-35 years) and older adults (>55 years).
- Slight male predominance.
- Risk factors: Epstein-Barr Virus (EBV) infection, family history, immunosuppression (e.g., HIV, post-transplant patients).
Clinical Presentation
- Painless lymphadenopathy (most commonly cervical, supraclavicular, or mediastinal).
- B symptoms (fever >38°C, drenching night sweats, weight loss >10% in 6 months) indicate advanced disease.
- Pruritus and alcohol-induced lymph node pain are less common but characteristic.
- Splenomegaly, hepatomegaly, or organ involvement in advanced disease.
Diagnosis
- Lymph node biopsy (excisional preferred) showing Reed-Sternberg cells in a mixed inflammatory background.
- Immunohistochemistry: CD30+ and CD15+.
- Staging investigations:
  - CT/PET scan – Determines extent of disease.
  - Bone marrow biopsy – Not routinely required
  - Blood tests: ESR, LDH, FBC (may show anaemia, leukocytosis, eosinophilia).
Staging (Ann Arbor Classification)
- Stage I: Single lymph node region.
- Stage II: Multiple lymph node regions on the same side of the diaphragm.
- Stage III: Lymph nodes on both sides of the diaphragm.
- Stage IV: Disseminated involvement (e.g., liver, bone marrow).
Management
- Early-stage disease (I-II): Further classified into favourable and unfavourable based on factors such as bulky disease, high ESR, extranodal involvement, and multiple nodal sites.
- Advanced-Stage disease (IIB-IV)
- Treatment options include chemotherapy and radiotherapy.
- ABVD or escalated BEACOPP: depending on stage and fitness of patient.
- Relapsed/refractory disease: Salvage chemotherapy, autologous stem cell transplant, and checkpoint inhibitors (e.g., pembrolizumab) for resistant cases.
Prognosis
- Highly curable, with >90% survival in early-stage disease.
- Poorer prognosis with B symptoms, bulky disease, and extranodal involvement.
Hodgkin Lymphoma is a curable malignancy with well-defined treatment strategies. Prompt diagnosis and staging are key to achieving excellent outcomes.

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March 19, 2025
Acute vs Chronic Leukaemia – A Brief Overview
Leukaemia is a group of malignancies affecting the bone marrow and blood, characterised by the uncontrolled proliferation of abnormal white blood cells. It is broadly classified into acute and chronic types, which differ significantly in presentation, pathophysiology, and management. This guide provides a structured overview to help junior doctors navigate the diagnosis and treatment of leukaemia.

Classification of Leukaemia

Leukaemias are divided based on cell lineage (myeloid vs lymphoid) and disease course (acute vs chronic):
- Acute Myeloid Leukaemia (AML): Rapidly progressive cancer of myeloid progenitor cells.
- Acute Lymphoblastic Leukaemia (ALL): Rapidly progressive cancer of lymphoid progenitor cells.
- Chronic Myeloid Leukaemia (CML): Slow-growing cancer of myeloid cells.
- Chronic Lymphocytic Leukaemia (CLL): Slow-growing cancer of lymphoid cells.
Pathophysiology
- Acute leukaemias arise from immature precursor cells (blasts), leading to uncontrolled proliferation and bone marrow failure.
- Chronic leukaemias involve the accumulation of more mature but dysfunctional cells, leading to a slower disease progression.
Clinical Presentation

Acute Leukaemias (AML & ALL)
- Rapid onset over weeks to months.
- Symptoms of bone marrow failure, including anaemia (fatigue, pallor), neutropenia (infections), and thrombocytopenia (bleeding, bruising).
- Systemic symptoms such as fever, weight loss, and night sweats.
- ALL can involve the central nervous system (CNS), causing headaches, seizures, and neurological deficits.
Chronic Leukaemias (CML & CLL)
- Insidious onset over years, often detected incidentally on routine blood tests.
- Fatigue, weight loss, and night sweats.
- Lymphadenopathy and splenomegaly, especially in CLL.
- CML may present with abdominal discomfort due to splenomegaly and a high white cell count.
Investigations

Acute Leukaemia
- Full blood count (FBC): High or low white cell count with circulating blasts; anaemia and thrombocytopenia are common.
- Blood film: Presence of blasts.
- Bone marrow biopsy: Confirms diagnosis with >20% blasts.
- Cytogenetics: Identifies translocations such as PML-RARA in acute promyelocytic leukaemia (APL).
Chronic Leukaemia
- FBC: Leukocytosis in CML; lymphocytosis in CLL.
- Blood film: Smudge cells in CLL; left shift (immature myeloid cells) in CML.
- Bone marrow biopsy: Hypercellular marrow with mature cells.
- Cytogenetics: BCR-ABL fusion gene in CML.
Management

Acute Myeloid Leukaemia (AML)
- Intensive chemotherapy with daunorubicin and cytarabine.
- Bone marrow transplantation for high-risk or relapsed cases.
Acute Lymphoblastic Leukaemia (ALL)
- Multi-agent chemotherapy.
- CNS prophylaxis with intrathecal methotrexate.
- Bone marrow transplant for high-risk patients.
Chronic Myeloid Leukaemia (CML)
- First-line treatment with tyrosine kinase inhibitors (TKIs) such as imatinib or dasatinib.
- Long-term suppression of disease with excellent survival rates.
Chronic Lymphocytic Leukaemia (CLL)
- Early-stage disease is often observed without treatment.
- Symptomatic or high-risk disease is treated with targeted therapies like BTK inhibitors (ibrutinib) or BCL-2 inhibitors (venetoclax), often combined with monoclonal antibodies like rituximab or obinutuzumab.
Prognosis
- Acute leukaemias progress rapidly and require urgent treatment. Survival rates vary: AML has a 40-50% survival rate in younger patients but much lower in the elderly. ALL has a 70-90% survival rate in children but lower in adults.
- Chronic leukaemias progress slowly and are often manageable for years. CML has an excellent prognosis with TKIs, with >90% five-year survival. CLL is highly variable, with some patients living decades without treatment.
Key Takeaways for Junior Doctors
- Acute leukaemias present with bone marrow failure and require urgent treatment.
- Chronic leukaemias are often incidental findings and may not need immediate therapy.
- Blasts in blood and bone marrow (>20%) suggest acute leukaemia.
- CML is driven by BCR-ABL and treated with TKIs.
- CLL is often indolent but requires treatment in high-risk cases.
Leukaemia is a complex but fascinating field in haematology. Junior doctors play a vital role in recognising its presentation, initiating investigations, and understanding treatment pathways.

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March 13, 2025
Chronic Lymphocytic Leukaemia (CLL) – A Junior Doctor’s Guide
Chronic Lymphocytic Leukaemia (CLL) is the most common adult leukaemia in Western countries. It is a clonal disorder of mature B lymphocytes and has a highly variable clinical course, ranging from an indolent disease requiring no treatment to aggressive forms necessitating early intervention. This guide provides an overview of CLL for junior doctors rotating through haematology.

Understanding CLL

CLL is characterised by the accumulation of small, mature-looking but dysfunctional B lymphocytes in the blood, bone marrow, and lymphoid tissues. It is closely related to small lymphocytic lymphoma (SLL), with the distinction being that CLL primarily affects peripheral blood, whereas SLL involves lymphoid organs.

Clinical Presentation

CLL can be asymptomatic and detected incidentally on a routine full blood count. Symptomatic patients may present with:
- Lymphadenopathy – Most common initial presentation.
- Hepatosplenomegaly – Occurs in advanced disease.
- Recurrent infections – Due to immune dysfunction and hypogammaglobulinaemia.
- Fatigue & Weight Loss – B symptoms in more aggressive disease.
- Autoimmune Complications – Autoimmune haemolytic anaemia (AIHA) and immune thrombocytopenia (ITP).
Investigations
- Full Blood Count (FBC) & Blood Film – Lymphocytosis (>5 × 10⁹/L) with small mature lymphocytes and smear (smudge) cells.
- Flow Cytometry – Confirms clonal B-cell population with CD5, CD19, CD20 (dim), and CD23 positivity.
- Bone Marrow Aspirate & Biopsy – Not always required but shows increased lymphocytes.
- Cytogenetics & Molecular Testing – Prognostic markers:
  - FISH for del(13q), del(11q), del(17p) (p53 mutation – poor prognosis).
  - IGHV mutation status (mutated = better prognosis, unmutated = worse prognosis).
- Immunoglobulin Levels – Assesses hypogammaglobulinaemia.
Staging

Two staging systems guide prognosis and treatment decisions:
- Rai Staging (USA):
  - 0: Lymphocytosis only (low risk).
  - I-II: Lymphadenopathy and/or organomegaly (intermediate risk).
  - III-IV: Anaemia and/or thrombocytopenia (high risk).
- Binet Staging (Europe):
  - A: <3 lymphoid areas involved.
  - B: ≥3 lymphoid areas involved.
  - C: Anaemia and/or thrombocytopenia.
Management

Management depends on disease stage, symptoms, and genetic markers. Many patients do not require immediate treatment and are monitored under a watch and wait approach.

Supportive Care
- Infection Prevention – Vaccination (e.g., pneumococcal, influenza), IV immunoglobulin for recurrent infections.
- Autoimmune Cytopenias – Managed with steroids, rituximab, or immunosuppressants.
- Blood Transfusions – Symptomatic anaemia or thrombocytopenia.
Definitive Treatment
1. Indications for Treatment
  - Symptomatic disease (B symptoms, bulky lymphadenopathy, organomegaly).
  - Progressive marrow failure (anaemia or thrombocytopenia).
  - Rapid lymphocyte doubling time (<6 months).
  - Severe autoimmune complications unresponsive to steroids.
2. First-Line Therapy
  - Targeted Therapy (preferred):
    
    Bruton’s tyrosine kinase (BTK) inhibitors: Ibrutinib, Acalabrutinib.
    
    BCL-2 inhibitors: Venetoclax (often combined with anti-CD20 monoclonal antibodies like rituximab or obinutuzumab).
  - Chemoimmunotherapy (for selected fit patients with IGHV-mutated disease and no TP53 mutation):
    
    FCR regimen (Fludarabine, Cyclophosphamide, Rituximab) – Younger patients.
    
    Bendamustine + Rituximab – Older or frail patients.
    
    Note this is (extremely) rarely used in the modern era
3. Relapsed/Refractory CLL
  - BTK inhibitors (Ibrutinib, Acalabrutinib) or BCL-2 inhibitors (Venetoclax) if not used first-line.
  - PI3K inhibitors (e.g., Idelalisib) in selected cases.
  - Allogeneic stem cell transplantation for high-risk, refractory disease.
Palliative Care
- For elderly or frail patients with slow disease progression, best supportive care is often appropriate.
- Symptom management with transfusions, steroids for autoimmune cytopenias, and infection prophylaxis.
- Clear goals-of-care discussions, particularly in advanced disease.
Complications to Watch For
- Infections – Bacterial, viral (zoster), and fungal due to immunosuppression.
- Tumour Lysis Syndrome (TLS) – Need to assess TLS risk and institute management as required when starting venetoclax.
- Richter’s Transformation – Transformation to an aggressive lymphoma (diffuse large B-cell lymphoma); suspect in rapidly enlarging lymph nodes or new B symptoms.
- Autoimmune Cytopenias – Haemolytic anaemia or thrombocytopenia.
- Secondary Malignancies – Increased risk due to immune dysfunction and prior treatments.
Prognosis and Follow-Up
- Indolent cases may never require treatment and have a normal life expectancy.
- Patients with TP53 mutations, del(17p), or unmutated IGHV have a poorer prognosis and require novel targeted therapies.
- Regular follow-up includes monitoring blood counts, lymphadenopathy, and signs of transformation or progression.
Key Takeaways for Junior Doctors
1. CLL is often asymptomatic and detected incidentally.
2. Flow cytometry confirms the diagnosis by demonstrating a clonal B-cell population.
3. Many patients follow a watch and wait approach, with treatment initiated only when clinically necessary.
4. Targeted therapies (BTK and BCL-2 inhibitors) have replaced chemotherapy for most patients.
5. Recognising Richter’s transformation and autoimmune complications is crucial for prompt intervention.
6. Palliative care should be considered for frail patients with advanced disease.
CLL is a fascinating and heterogenous disease with a rapidly evolving treatment landscape. Junior doctors play an essential role in recognising its presentation, monitoring progression, and initiating appropriate management.

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March 12, 2025
Acute Lymphoblastic Leukaemia (ALL) – A Junior Doctor’s Guide
Acute Lymphoblastic Leukaemia (ALL) is an aggressive haematological malignancy resulting from the clonal proliferation of lymphoid precursor cells (blasts). It is more common in children but also occurs in adults, with prognosis and management differing by age group. Early recognition and timely intervention are key to improving patient outcomes. This guide provides an overview of ALL for junior doctors rotating through haematology.

Understanding ALL

ALL arises from malignant transformation of lymphoid progenitor cells, leading to uncontrolled proliferation and bone marrow failure. It is broadly classified into B-cell ALL (B-ALL) and T-cell ALL (T-ALL) based on the cell lineage of origin. Genetic and molecular features further stratify risk and guide treatment decisions.

Clinical Presentation

Patients with ALL often present with symptoms related to bone marrow failure and organ infiltration:
- Anaemia – Fatigue, pallor, dyspnoea
- Neutropenia – Recurrent infections, fever
- Thrombocytopenia – Easy bruising, petechiae, mucosal bleeding
- Lymphadenopathy & Hepatosplenomegaly – More common in T-ALL
- Mediastinal Mass – T-ALL often presents with a mediastinal mass causing respiratory distress or superior vena cava syndrome (SVCS)
- Neurological Symptoms – Headache, cranial nerve palsies, or seizures due to central nervous system (CNS) involvement
Investigations

A structured approach is crucial when suspecting ALL. Essential investigations include:
- Full Blood Count (FBC) & Blood Film – Shows anaemia, thrombocytopenia, and lymphoblasts.
- Bone Marrow Aspirate & Biopsy – Confirms the diagnosis with >20% lymphoblasts in the marrow.
- Immunophenotyping (Flow Cytometry) – Differentiates B-ALL from T-ALL.
- Cytogenetics & Molecular Testing – Identifies key mutations (e.g., Philadelphia chromosome t(9;22), TEL-AML1, MLL rearrangements) for prognosis and targeted therapy.
- Lumbar Puncture – Evaluates for CNS involvement.
- Coagulation Studies – Important in cases with disseminated intravascular coagulation (DIC).
- Chest X-ray/CT – Checks for a mediastinal mass in T-ALL.
Management

Management of ALL is intensive and consists of several phases:

Supportive Care
- Blood Product Support – Red cell and platelet transfusions as needed.
- Infection Control – Empirical broad-spectrum antibiotics for febrile neutropenia, antifungal and antiviral prophylaxis in high-risk cases.
- Tumour Lysis Syndrome (TLS) Prophylaxis – Hydration, allopurinol, or rasburicase to prevent TLS.
Definitive Treatment
1. Induction Therapy (Aim: Achieve remission)
  - Multi-agent chemotherapy including vincristine, steroids (dexamethasone or prednisolone), anthracyclines (e.g., doxorubicin), and asparaginase.
  - CNS-directed therapy with intrathecal methotrexate.
2. Consolidation (Intensification) Therapy (Aim: Eradicate residual disease)
  - High-dose methotrexate, cytarabine, and additional systemic chemotherapy.
  - Targeted therapies for specific subtypes (e.g., tyrosine kinase inhibitors [TKIs] for Philadelphia chromosome-positive ALL).
3. Maintenance Therapy (Aim: Prevent relapse)
  - Long-term low-intensity chemotherapy (e.g., mercaptopurine, methotrexate) for 2-3 years, especially in paediatric protocols.
4. Stem Cell Transplantation
  - Considered in high-risk or relapsed cases, particularly in adult ALL.
5. Targeted Therapy
  - TKIs (e.g., imatinib, dasatinib) for Philadelphia chromosome-positive ALL.
  - Monoclonal antibodies (e.g., blinatumomab, inotuzumab) for relapsed or refractory disease.
Palliative Care
- In patients who are unfit for intensive therapy due to age, comorbidities, or frailty, supportive care focuses on symptom management and quality of life.
- Transfusions for anaemia-related symptoms, infection control, and pain management are key.
- Clear discussions about goals of care and advanced care planning should be undertaken.
Complications to Watch For
- Febrile Neutropenia – Requires urgent broad-spectrum antibiotics.
- Tumour Lysis Syndrome (TLS) – Can lead to acute kidney injury and metabolic derangements.
- Disseminated Intravascular Coagulation (DIC) – Common in hyperleukocytosis.
- CNS Involvement – Requires intrathecal chemotherapy.
- Relapsed/Refractory Disease – May require novel therapies or stem cell transplantation.
Prognosis and Follow-Up
- Prognosis is better in children, with cure rates exceeding 80%.
- Adults have a lower survival rate, especially in high-risk subtypes.
- Long-term follow-up includes:
  - Monitoring for late effects of chemotherapy (e.g., secondary malignancies, cardiotoxicity).
  - Surveillance for relapse with periodic blood tests and bone marrow biopsies.
Key Takeaways for Junior Doctors
1. Consider ALL in patients with pancytopenia and circulating lymphoblasts.
2. Early initiation of supportive care, including infection control and TLS prophylaxis, is crucial.
3. ALL management involves multiple chemotherapy phases and is highly protocol-driven.
4. Recognising complications such as febrile neutropenia and mediastinal masses can be life-saving.
5. Palliative care is an important consideration for patients unsuitable for intensive therapy.
ALL is a complex but treatable disease, particularly with advances in targeted therapies and stem cell transplantation. Junior doctors play a key role in initial diagnosis, supportive care, and recognising complications.

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March 10, 2025