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Haematological Cancers

Learning Targets and Key Concepts

• Understand the cell of origin for haematological cancers.
• Understand the key differences between leukemias and lymphomas.
• Gain a general understanding of the different types of leukemias and lymphomas.
• Knowledge of the relative incidence of different haematological disorders.
• Understand the difference between myeloproliferative disorders (MPNs), myelodysplastic syndrome (MDS), and leukemia.
• Understand the differences between chronic (CML, CLL) and acute leukemias (AML, ALL).
• Understand that developments in targeted therapy made in blood cancers have paved the way for new targeted therapies in solid tumors (e.g., rituximab, ibrutinib, midostaurin).
• Understand the concept of minimal residual disease (MRD) and its importance for prognosis and disease monitoring.

Normal Hematopoiesis

• Hematopoiesis = blood cell production.
• All formed elements of blood (red blood cells, granulocytes, monocytes, platelets, and lymphocytes) have a common origin from hematopoietic stem cells (HSCs) within the bone marrow.
• HSCs: Pluripotent stem cells at the apex of a hierarchy of bone marrow progenitors.
• Development of mature blood cells from HSCs involves progressive commitment to increasingly specialized cell populations.

Haematopoietic/Blood Cancers

• Blood cancers develop from the accumulation of genetic mutations in cells of the hematopoietic system.
• Clonal diseases.
• Types:
  • Lymphomas
  • Leukemias
  • Myeloma
  • Myeloproliferative disorders
  • Myelodysplastic syndrome

Lymphomas

• Neoplastic disease of mature lymphocytes.
  • Hodgkin Lymphoma (HL)
  • Non-Hodgkin Lymphoma (NHL)

Acute Leukemia

• Neoplastic disease of immature cells (blasts) in the bone marrow.
  • Acute myeloid leukemia (AML)
  • Acute lymphoid leukemia (ALL)

Chronic Leukemia

• Neoplastic disease of mature white blood cells in the bone marrow.
  • Chronic myeloid leukemia (CML)
  • Chronic lymphoid leukemia (CLL)

Myeloma / Multiple Myeloma

• Neoplastic disease of plasma cells.

Myeloproliferative Diseases

• Group of neoplastic disorders involving the bone marrow cells that produce red blood cells, platelets, or fibroblasts.
• Overproduction of fibroblasts within the bone marrow that produce extracellular matrix (e.g., collagen).

Myelodysplasia / Myelodysplastic Syndrome (MDS)

• Pre-cancerous disease of the bone marrow, where the dysplastic cells may cause abnormal or inadequate blood cell production.

Incidence and Mortality of Haematological Cancers

• Blood cancers combined are:
  • 2nd most diagnosed cancers in Australia.
    • 17,321
  • 2nd highest cause of cancer-related deaths in Australia.
    • 5,631
  • The most common diagnosed childhood cancer (aged 0-14 years), accounting for ~30% of all childhood cancer diagnoses (ALL most common).
• 30% increase in incidence rates of blood cancer over the past decade.
• This year:
  • >18,000 Australians diagnosed with a blood cancer
  • >5,700 Australians will die from a blood cancer
  • >110,000 Australians living with blood cancer.
• Incidence predicted to > double by 2035 (~36,000 p.a.).
• Lymphoma is the most common overall.
• ALL is the most common childhood cancer.
• For most blood cancers, incidence increases with age.

Symptoms of Blood Cancers

• Symptoms differ depending on the type of blood cancer.
• Generally result from reduced or abnormal production of normal hematopoietic cells:
  • Red blood cells (carry $O_2$ around the body):
    • Anemia
    • Fatigue or weakness
    • Shortness of breath
  • White blood cells (fight infections & play roles in inflammation):
    • Fever
    • Increased infections
  • Platelets (blood clotting):
    • Easy bleeding & bruising
  • Swollen lymph glands (lymphoma)
  • Painful bones (myeloma)

Diagnosis of Blood Cancers

• Bone marrow biopsy & peripheral blood collection:
  • Differential blood counts
  • Morphological analysis of white blood cells
  • Cytogenetics
  • qPCR
  • Gene sequencing

Traditional Treatment of Blood Cancers

• Blood cancers are disseminated diseases from the outset.
• Surgery or radiotherapy is not often used.
• Chemotherapy: Mainstay treatment +/- addition of newer therapies
  • Targeted therapies
  • Immunotherapies

Chemotherapy

• Chemotherapy kills rapidly dividing cells.
• Commonly used chemotherapy in blood cancers:
  • Alkylating agents (e.g., cyclophosphamide): Cross-links DNA and RNA.
  • Antitumor antibiotics (e.g., Daunorubicin): Interchelates into DNA, inhibiting topoisomerase II ability to replicate DNA.
  • Antimicrotubule agents (e.g., vincristine): Bind to microtubules, inhibiting microtubule dynamics and hence mitosis.
• The last decade has seen chemotherapy combined with targeted therapies.

Bone Marrow Transplants (BMT) / Stem Cell Transplants

• Involves the transplant of healthy hematopoietic stem cells into a patient after they have undergone intensive chemotherapy to kill their leukemia cells (but also kills their HSCs).
  • Autologous bone marrow transplant: Stem cells are harvested from the patient themselves and given back to them after the patient has had intensive chemotherapy treatment.
  • Allogeneic bone marrow transplant: A donor with the same genetic type as a patient (usually a sibling, parent, or unrelated donor) donates their stem cells.
  • Umbilical cord blood transplant: Stem cells are taken from the umbilical cord immediately after a healthy baby’s birth. They are then tested and frozen until they’re needed.
• For most acute myeloid leukemias, BMT is still the only curative therapy; therefore, chemotherapy treatment for high-risk AML aims to ‘bridge to transplant’.

Lymphomas

• Cancer of the lymphatic system and lymphocytes.
• Lymphatics drain fluid and waste, and lymphocytes help fight infection.
• Develop outside of the bone marrow, often noticed as lumps in the lymph nodes where WBCs accumulate, or if lymphoma cells invade the bone marrow.
• Broadly divided into 2 groups:
  • Hodgkin Lymphoma
  • Non-Hodgkin Lymphoma
• WHO currently recognizes 43 subtypes of lymphoma!

Hodgkin Lymphoma (HL)

• 2 peaks of incidence by age:
  • 20-40 years
  • >75 years
• Risks:
  • Lowered immune system
  • HIV/AIDS
  • Autoimmune conditions (e.g., rheumatoid arthritis or systemic lupus)
  • Epstein Barr Virus infection (glandular fever)
  • Prior NHL
• Survival is very good:
  • Stage 1-2: 90% 5-year survival
  • Stage 3-4: 70-80% 5-year survival
• Treatment:
  • Chemotherapy in almost all cases:
    • ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)
  • Radiotherapy in some
  • BMT in some relapsed cases (rare)

Non-Hodgkin Lymphoma (NHL)

• Multiple subtypes, grouped broadly into:
  • Fast-growing - High-grade
  • Slow-growing - Low-grade
• Common NHLs:
  • Diffuse large B-cell lymphoma (high grade)
  • Follicular lymphoma (low grade)
  • Marginal zone lymphoma
  • Mantle cell lymphoma
  • Burkitt lymphoma
• The majority of cases are B-cell lymphomas.
• A minority are T-cell lymphomas.
• Treatment:
  • Aim is complete remission (cure)
  • Chemotherapy – CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)
  • Plus anti-CD20 antibody (e.g., Rituximab)
  • Sometimes RT or BMT
  • Low-grade lymphomas: Often no treatment – active monitoring or intermittent treatment

Rituximab – Targeted Antibody Therapy

• Monoclonal antibodies that are targeted to detect and bind a protein on the surface of the cancer cell; signals the immune system to recognize and kill the cell.
• Rituximab:
  • Binds CD20 found on B cells
  • Used in various NHLs and CLL
  • The first drug that successfully targeted proteins on cancer cells (FDA approval in 1997).
  • Many others followed (e.g., Herceptin (anti-HER2); Cetuximab (anti-EGFR))

Proteasome Inhibitors

• Proteasome:
  • Regulated degradation of proteins that are damaged or no longer needed.
  • Proteasome inhibition results in toxic buildup of proteins, leading to cell death.
• Bortezomib:
  • The first proteasome inhibitor used in clinical practice (approved by FDA in 2003 for MM).
  • Inhibits the proteasome.
  • Targets malignant cells and microenvironment.
  • Used to treat:
    • Mantle cell lymphoma (a low-grade lymphoma)
    • Multiple myeloma

Myeloma / Multiple Myeloma

• Mainly a disease of older age.
• Massive expansion of the malignant plasma cell clone.
• Plasma cells usually produce antibodies (G, A, M, D, and E).
• Myeloma cells produce large amounts of immunoglobulins – paraprotein – sticky blood.
• Paraprotein levels used for diagnosis and monitoring.
• Displacement of other BM cells – anemia, infections.
• Bone fractures & kidney problems also common in myeloma.

Leukemias

• Leuk = white; aemia = in blood.
  • Acute Leukemia: Neoplastic disease of immature cells (blasts) in the bone marrow.
    • Acute myeloid leukemia (AML)
    • Acute lymphoid leukemia (ALL)
  • Chronic Leukemia: Neoplastic disease of mature white blood cells in the bone marrow.
    • Chronic myeloid leukemia (CML)
    • Chronic lymphoid leukemia (CLL)

Chronic Lymphoblastic Leukemia (CLL)

• Most common chronic leukemia (~1,000 cases/year in Australia).
• ~80% of cases occur in people >60 years of age.
• Caused by various genetic mutations.
• Too many B lymphocytes, which crowd out other cells in the BM.
• Lymphocytes don’t work well.
• ‘Smudge/Basket cells’ – characteristic of CLL – fragile cells that smudge on blood smear prep.
• Good survival – 85% at 5 years.
• Prognosis depends on mutation:
  • IgVH region mutation – 20-year median survival
  • Del(17p) – 7-year medial survival
• Treatment:
  • No treatment at the early stage
  • Later stage – chemotherapy + targeted therapies (e.g., ibrutinib, venetoclax, rituximab)

Chronic Myeloid Leukemia (CML)

• Less common than CLL.
• ~330 Australians diagnosed with CML / year.
• More common in adults >40 years.
• Risk factors:
  • Very high dose radiation (nuclear accident; prior RT treatment)
  • Chemicals (e.g., benzene; high dose chemotherapy)
• Develops gradually during the early stages of disease and progresses slowly over weeks or months.
• The natural course of the disease has 3 phases:
  • Chronic phase
  • Accelerated phase
  • Blast phase (blast crisis) – acute leukemia

Philadelphia Chromosome in CML

• CML is driven by a translocation between chromosome 9 and 22 - Philadelphia chromosome – BCR/ABL fusion gene.
• Results in constitutive activation of the ABL tyrosine kinase and activation of downstream growth/survival pathways (RAS/ERK; PI3K/AKT, STAT; MYC).
• The first small molecule targeted therapy directed to BCR/ABL - Imatinib.

Imatinib (Gleevec)

• Breakthrough because it was the first successful small molecule targeted therapy – new era in cancer therapy.
• By understanding how the CML cell works, enabled ‘drug by design’ development to inhibit the ATP-binding site of BCR/ABL.

Transformational Effect of Imatinib on CML Patient Outcomes

• Now measure Major Molecular Response (qPCR for BCR/ABL).
• If achieve complete molecular response, progression-free survival is 100% (i.e., no progression to blast crisis phase).
• Monitor BCR/ABL levels for minimal residual disease (MRD).
• Imatinib works for most people for years.
• Many patients can stop therapy - monitor for MRD.
• Resistance can develop – often due to mutation in ‘gatekeeper’ amino acid T315.
• 2nd and 3rd generation TKIs if resistance to imatinib develops.

Acute Myeloid Leukemia (AML)

• >900 diagnoses per year in Australia.
• Poor survival – 25% overall; 5-15% in patients aged >65 years.
• Characterized by differentiation arrest and uncontrolled clonal proliferation of neoplastic immature precursors.
• Unlike CML, AML is highly heterogeneous, with multiple clones driven by multiple mutations.
• Outcome is determined by the genetic mutations/chromosome aberrations present.
• Understanding functional AML subsets can inform rational treatment strategies.
• The predominant clone at diagnosis may not be the predominant clone at relapse.
• Treatment – combination chemotherapy (daunorubicin and cytarabine) +/- targeted therapy.
• Recurrent somatic mutations in AML found mostly in transcription factors, kinase signaling molecules, and epigenetic regulators.

Targeting FLT3 Mutant AML

• The most common mutation in AML (~35%) occurs in the Fms-like tyrosine kinase 3 (FLT3) gene.
• Type III receptor tyrosine kinase (RTK) expressed in hematopoietic progenitor cells and dendritic cells.
• Activated by FLT3-ligand (FL) and regulates differentiation, proliferation, and survival (PI3K/AKT, Ras/ERK, STAT pathways).
• The most common mutations are internal tandem duplications (ITD) and kinase domain mutations.
• FLT3-ITD correlates with increased risk of relapse and dismal survival.
• Can be targeted with small molecule TKIs (e.g., Midostaurin).
• Clinical trials of FLT3 inhibitors as single agents were disappointing.
• Short term and/or partial responses in a minority of patients.
• Rapid selection of drug-resistant clones – often due to secondary mutations in FLT3 tyrosine kinase domain (FLT3-TKD).
• FLT3i in combination with standard therapy improves AML survival – RATIFY trial.
• Midostaurin – 1st FDA-approved mutation-targeted therapy in AML.
• Novel combinations of FLT3i’s with other targeted therapies are currently being tested.

Acute Lymphoblastic Leukemia (ALL)

• Most common childhood cancer.
• A large number of immature lymphocytes.
• Fatal in weeks – months if not treated.
• Introduction and improvements to combination chemotherapy have led to improved survival:
  • \
  • Survival much worse in pts >60 years
• ALL is mainly a disease of children – 2-5 years is the most common age; rare after 24 years.
• Long-term survivors have significant complications caused by treatments.
• The focus now is on reducing the toxicity of treatments.
• E.g., reducing the dose of combination chemotherapy based on individual risk stratification and MRD monitoring.

Summary & Key Take Home Messages

• See above for classifications of:
  • Lymphomas
  • Acute Leukemia
  • Chronic Leukemia
  • Multiple Myeloma
  • Myeloproliferative Diseases
  • Myelodysplasia / Myelodysplastic Syndrome (MDS)
• Many hematological cancers are treated as chronic diseases with excellent long-term survival.
• Acute myeloid leukemia still needs major therapeutic advancements to improve survival.
• Hematological cancers have been the ‘poster child’ for the development of targeted therapies (e.g., Rituximab, Ibrutinib, Midostaurin).