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Perth Haematology :: Dr Steven Ward

Acute Myeloid Leukaemia (AML)                                                APML (AML M3)

AML Prognosis at 1st Relapse

AML Therapy Algorithm

AML is a highly malignant cancer of the blood and marrow.

There are many types of AML, most recently classified by WHO.

 

 

AML CLASSIFICATION

AML with genetic defects AML with t(8;21)   AML1-ETO
AML with abnormal eosinophils inv (16) or t(16;16)    CBFB-MYH11
AML with t(15;17)      PML-RARa and variants
AML with 11q23     abn MLL
AML with dysplasia AML with trilineage dysplasia - prior MDS
AML with trilineage dysplasia - de novo
Therapy-related AML AML therapy related - alkylator
AML therapy related - Topisomerase II inhibitor
AML not otherwise specified (based on FAB) AML NOS minimally differentiated [M0]
AML NOS without maturation [M1]
AML NOS with maturation [M2]
AML NOS acute myelomonocytic [M4]
AML NOS acute monoblastic & monocytc [M5]
AML NOS acute erythroid leukmaemia [M6]
AML NOS acute megakaryoblastic [M7]
Other AML AML NOS acute basophilic
AML NOS acute panmyelosis with myelofibrosis [acute myelofibrosis]
AML NOS myeloid sarcoma [chloroma]
AML of ambigious lineage

NOS = Not Otherwise Specified

AML prognosis depends on a number of factors. These include:

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whether the disease is de novo AML (or primary) where there is no preceding haematological disorder or chemotherapy or secondary AML arising from a pre-existing haematological disorder (such as MDS) or chemotherapy for other cancers (including breast cancer, NHL therapy etc)

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de novo AML has a better prognosis

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Patient's age

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Older age tends to reduce the prognosis

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<60 years: CR rate of 75-85% and 5 year survival of 40%

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>60 years: CR rate of 45-55% and 5 year survival of 10-20%

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Subtype of AML

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Acute Promyelocytic Leukaemia, AML with t(8,21) and AML with inv (16) have a better outlook (CR >90%, 5 year survival 65%)

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10% have adverse cytogenetics: -7, -5, -5q, comlex

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60% are intermediate risk: all others (CR 80%), 5 year survival 30-40%)

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Other co-exisiting disorders

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lung, heart disease etc

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New potential prognostic markers

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MDR-1 espression; FLT3 mutations (poorer prognosis)

 

Without treatment AML usually progresses rapidly to death within a few weeks.

Some patients have smouldering AML which causes marrow failure with low blood counts (pancytopenia) without excessive blasts circulating in the blood. The marrow confirms AML but for some unknown reasons it does not progress quickly. instead it grumbles along for a number of months, but will eventually accelerate with rising blast cell counts.

 

Around 80-85% of patients will achieve complete remission (CR) after induction chemotherapy (see below). This means that the disease is not detectable in routine tests of the blood and marrow. However the disease is still present, just not detectable. Further therapy is required to try to eradicate the disease and provide longer-term freedom from disease. Approximately 40% of patients with de novo AML will still be alive after 5 years. After this time the disease is generally cured.

 

With secondary AML the outlook is less less encouraging, with a complete remission rate of 50-70%, and 5-year survival of 20%.

 

Relapsed AML (is recurrent disease after successful initial therapy) has a grim prognosis.

 

AML Clinical Features:

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See Introduction to Leukaemia

 

 

AML Therapy

Age, functional status, other medical problems and patient preference are all used to determine the best approach for each individual. There are 4 main approaches:

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Induction chemotherapy: intense chemotherapy aimed at trying to eradicate the disease.

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Less-intense chemotherapy given to achieve remission, generally in older age groups.

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Gentle oral chemotherapy used to help relieve symptoms but not aimed at trying to achieve cure or disease remission.

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Palliative therapy to ensure the remaining time is of good quality.

 

AML Therapy Algorithm (pdf)

 

Induction Chemotherapy and consequences

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A central line (central venous catheter CVC) is inserted to allow semi-permanent access to veins for giving chemotherapy, blood, antibiotics, fluid etc; and also for collecting daily blood samples. This is usually inserted under local anaesthetic either under the collar bone or in the neck. A CVC will provide comfort by preventing the need for continually changing of drip sites and having needles for blood tests.

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Intravenous chemotherapy (see also page on Introduction to chemotherapy) is administered over 5-7 days. A combination of several drugs are used.

Chemotherapy generally works by killing cells which are actively growing and dividing.

Hence some of the side effects are  related to the fact that most chemotherapy is not specific for tumour cells, but will kill any cell in the process of dividing (into 2 daughter cells). This commonly affects the marrow cells, hair, and lining of the gut.

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Chemo used to cause marked nausea and vomiting. This is much less of a problem due to excellent anti-sickness drugs (anti-emetics).

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During the chemotherapy there is usually no major problems. However following the therapy the blood counts drop towards zero and the effects on other tissues takes effect:

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Marrow suppression:

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Very low white cells: high-risk of infection; almost all patients will develop infection (sepsis, septicaemia). Intravenous antibiotics are used to keep the infection under control until such time that the white cells regenerate and are able to finally eradicate the infection. High fevers and sweats are common.

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Anaemia (low Hb): frequent blood transfusion is required after chemotherapy.

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Very low platelets (thrombocytopenia): high-risk of bleeding; platelet transfusions are provided to reduce this risk; bruising is usual.

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Mucositis: raw gut-lining: this affects the whole gut from mouth to anus. A painful mouth, mouth ulcers and difficulty swallowing can occur. Abdominal pain, cramps and diarrhoea can occur. Sometimes bleeding occurs from the gut too. These are treated by reducing or ceasing food intake, strong pain-killing agents and diarrhoea medications.

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Alopecia: hair loss is inevitable. It will regrow once all the therapy is complete.

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Sometimes there are side effects of the many drugs used to treat AML or its consequences (eg antibiotics): these include allergic reactions, skin rash, liver inflammation, kidney impairment, etc.

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When the marrow starts to regenerate after 3-4 weeks from the 1st day of therapy (3 weeks from the end of therapy) all the problems start to heal and disappear. The fevers subside, mouth and gut heal and the person starts to feel better. Once the blood counts are rising and at safe levels, the patient is allowed home for a week or so. This usually occurs after a month in hospital.

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After  a week at home, readmission and reassessment of the AML is required. Repeat bone marrow studies are done to determine if remission is achieved, or how well the therapy has worked. No matter the marrow results, further therapy is required if prolonged remission and potential cure is desired.

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If remission is achieved two further cycles of chemotherapy - called consolidation therapy - are given. These are similar tot he induction therapy but of shorter duration and sometimes lower doses of drugs are used. The consequences of consolidation therapy are very similar to those of induction therapy. Severe marrow suppression occurs, and sepsis is inevitable, with a 2-3 week hospital admission likely after each cycle.

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If the disease has partially responded to therapy, a second induction cycle is given, the followed by 2 cycles of consolidation therapy if remission is achieved after the 2nd induction.

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If the disease persists (ie no major reduction in disease following therapy) the outlook is not good. Alternative salvage therapy may be used (using drugs not previously administered) or palliative care commenced.

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Some patients die during therapy, from either persisting disease or overwhelming sepsis which is not able to be controlled despite effective iv antibiotic therapy.

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Following completion of therapy for AML, regular follow-up by the Haematologists will be provided on along-term basis. Usually blood tests are taken, physical examination performed to assess if remission continues, and to look for late effects of the therapy.

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Return to work is not usually considered for at least 6 months from the diagnosis, as patients are too weak.

 

Bone Marrow Transplant in AML

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BMT is not an initial therapy for AML.

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Transplantation is usually reserved for high-risk patients after achieving first remission or patients in remission after 1st relapse.

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Allogeneic BMT is the usual method - transplant using a compatible sibling

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Autologous BMT is rarely used - mainly as high-dose consolidation therapy in patients with high-risk of relapse who are not eligible for allogeneic transplant (because of lack of donor, age or ill-health)

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BMT is associated with major risks of ongoing side effects and death. It can however cure the disease.

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The usual procedure is to perform a family study of the patient's immediate family (parents and siblings, occasionally children). Blood tests are taken for tissue typing. If there is a compatible donor ("match")  this leaves the door open for potential BMT if it is needed.

 

Acute Promyelocytic Leukaemia (APML, AML M3)

 

 

Elderly AML

FLICC Flexible Low Intensity Chemotherapy :: ALLG AML10 Clinical Trial

 

Elderly AML >60 years

25 pts age 61 78

 

Mitoxantrone 6mg/m2 iv x 3 days

Cytarabine 10mg/m2 sc bd for 7-14 days

Etoposide 100mg oral daily for 7-14 days

 

52% CR

25% no response

24% died <30 days: infection, bleeding, leukaemia, renal failure

OS 6.5 months

Median remission duration 7.7 months

1 yr survival 32%; If achieve CR 64%

OS reduced if poor cytogenetics

 

 

Course 1

Course 2

Significant Neutropenia

19 days

6 days

Thrombocytopenia

11 days

5 days

Hospital

27 days

15 days

 

Similar outcomes to more aggressive protocols in the elderly; but less toxic.