HC25: Myeloid malignancies

Myeloid neoplasia

Myeloid malignancies are divided into 3 categories:

• Disorders of proliferation
  • Chronic myeloid leukemia
  • Myeloproliferative disorders
• Disorders of differentiation
  • Myelodysplastic syndromes
• Disorders of differentiation and proliferation
  • Acute myeloid leukemia

Chronic myeloid leukemia

Chronic myeloid leukemia is a disorder of proliferation → it is a stem cell disease.=

Case:

A 48-year-old male patient suffers from fatigue, but has no other complaints. Physical examination shows pallor and an enlarged spleen.

Laboratory tests:

A laboratory test shows:

• Hb: 8,0 mmol/L → too low
  • MCV (mean corpuscular volume): 96 fL
• Leukocytes: 113 x 10E9/L → too high
• Platelets: 154 x 10E9/L → normal

Leukocyte differentiation shows:

• 1 promyelocytes
• 10 myelocytes
• 8 metamyelocytes
• 8 band forms
• 53 segmented neutrophils

There shouldn’t be any promyelocytes, myelocytes and metamyelocytes present in the blood. The only cells that should be present are mature blood cells.

Diagnosis:

The diagnosis is Philadelphia chromosome positive chronic myeloid leukemia (CML). The driver mutation of CML is BCR/ABL, caused by a translocation of chromosome 9 and 22. This mutation causes cells to have a proliferative advantage. There is no mutation in differentiation genes → differentiation in mature stages is normal. Therefore, neutrophils are segmented as usual.

Mechanism:

Chromosome 9 contains the ABL gene, chromosome 22 contains the BCR gene. The mutation takes place as follows:

1. Both chromosomes break
2. The ABL gene attaches to the BCR gene on chromosome 22 → the Philadelphia chromosome is created
3. A constantly active tyrosine kinase is made
4. Multiple substrates are phosphorylated → multiple ways of absent regulation are made
5. Chronic myeloid leukemia arises

It is unknown why the translocation of chromosome 9 and 22 occurs. There is no relation with exposition to chemicals.

Epidemiology:

Chronic myeloid leukemia has a slowly progressive course and is a member of the myeloproliferative diseases:

• Forms 14% of all adult leukemias
• Incidence: 1-1,5/100.000
• Male : female = 2:1
• Median age: 53 years
  • There is an increase in younger patients

Symptoms:

Symptoms of chronic myeloid leukemia are:

• Fatigue and weight loss
• 40% asymptomatic → disease is detected by chance
• 50% splenomegaly (enlarged spleen)
• 20% hepatomegaly (enlarged liver)
• 50% anemia
• 20% thrombocytosis

Target therapy:

Due to the known mutated shape of BCR/ABL tyrosine kinase, there is a specific inhibitor which binds to the ADP spot of tyrosine kinase → cannot bind to ATP. This causes the signaling pathway to halt. Normally, ATP activates a signaling cascade causing absent regulation.

Course of the disease:

Chronic myeloid leukemia has 3 phases:

1. Chronic phases
2. Accelerated phase
   • >15% malignant blasts and promyelocytes
   • >20% basophils
   • <100 platelets
3. Additional cytogenic abnormalities are present
4. Blast phase: looks like acute leukemia
   • >20% blasts in the blood and bone marrow

Over time, the normal cells in the bone marrow are outcompeted by the mutated cells. In the later stages of the disease, the mutated cells mutate even more → the accelerated phase and blast phase. In the end, normal cells in the bone marrow are completely outcompeted by cancer cells.

Therapy:

Therapy of chronic myeloid leukemia consists of:

• TKIs (tyrosine kinase inhibitors)
  • Imatinib
  • 2^nd generation TKIs: dastinib, nilotinib
  • 3^rd and 4^th generation TKIs
• Allogenic stem cell transplantation
  • In case of:
    • Non-response to TKIs
    • Mutations in the binding pocket of BCR/ABL
    • Intolerance for TKIs
  • The allogenic donor can be:
    • An HLA identical sibling
    • MUD: matched unrelated donor
• Conventional chemotherapy: hydroxyurea, busulphan
  • Only when TKIs cannot be given due to intolerance of mutations in the gene

Acute myeloid leukemia

Acute myeloid leukemia (AML) is a disorder of differentiation and proliferation → there is a differentiation block and an increase of proliferation. It is a disease which typically has an older patient base → the peak is after the age of 60. Particularly the older patients die from it. Survival rates in general aren’t very high.

Etiology:

Multiple mutations are necessary to develop AML. Usually it is a combination of 2 types of mutations:

• Mutations giving proliferation advantages (class I)
• Mutations giving differentiation stops (class II)

The old concept of the leukomogenesis of AML was that DNA-damage causes a leukemic stem cell to arise which blasts daughter cells, which in turn are sensitive to chemotherapy. This isn’t correct.

Now it is known that multiple, subsequently acquired mutations are necessary to develop AML → multiple clones with multiple mutations are formed. Frequently, this is a combination of a mutation giving a proliferation advantage (class I) and mutations giving a differentiation stop (class II).  Class I mutations almost never combine with other class I mutations.

Therapy:

Because AML is made up of multiple, different clones, the prognosis differs. Therefore, not every clone is sensitive to chemotherapy. After chemotherapy, a small residue of clones are still present and proliferate → causes a relapse of AML. This is called minimal residue disease.

The goal of AML therapy is complete remission (CR) → <5% blasts in the bone marrow and a normal blood count.

Chemotherapy is still the most important treatment modality of AML. The therapy consists of 2 courses:

1. Remission-induction course: intensive chemotherapy
   • 60-90% chance of CR
   • Cytarabine, anthracycline
2. Consolidation course: stabilization of CR with intensive chemotherapy
   • High dose cytarabine + anthracycline

In case this doesn’t work, stem cell transplantation can be performed:

• Autologous stem cell transplantation: the patient is given a transplant of their own blood/bone marrow
• Allogenic stem cell transplantation
  • Myeloablative therapy: toxic
    • Complete eradication of the immune system
    • Not every patient is eligible
  • Non-myeloablative therapy: mild
    • Applicable up to 75 years of age

Mainly non-good risk AML patients are consolidated with allogeneic stem cell transplantation.

Complications of high dose chemotherapy are:

• Mucositis
• Infections
• Pancytopenia
  • All types of blood cells are diminished
  • Lasts for 3 weeks

In the last 15 years, there hasn’t been any improvement in the overall AML survival with conventional treatment.