Canterbury DHB

Treatment of non-trial patients

Patients who do not enter the AML19 APML trial will be treated with induction and consolidation as per the AIDA arm of the trial.

Management of Relapse or Refractory Patients

If a patient with APML relapses, reinduction with arsenic and tretinoin (ATRA) as per AML17 provides an excellent chance of achieving a molecular CR. If not in molecular remission at day 60, consider adding Idarubicin as per AIDA protocol. An autograft or allograft may now be appropriate treatments, as APML will almost certainly relapse if arsenic is not followed by further chemotherapy.

Patients who have only received arsenic and tretinoin (ATRA) should be treated with AIDA.

Arsenic Treatment

Arsenic, when given as a daily infusion, is effective in both de novo and relapsed APML, with a haematological CR of about 80%. It causes minimal haematological toxicity, though can be quite difficult to give consistently in some patients with borderline QTc intervals. Arsenic is effective against both tretinoin (ATRA) sensitive and resistant APML. Its mode of action is by the induction of apoptosis via its interaction with the PML-RARα fusion protein, which it degrades. During induction it is usually given daily for 4-6 weeks by IV infusion. In the consolidation phase, a number of different schedules have been used. It can be combined with tretinoin (ATRA) or chemotherapy. Prescription charts for Arsenic are available.

See also side effects of arsenic trioxide.

For full details of this treatment, see Mathews et al, 2006.

Administration

Arsenic trioxide comes in 10 mL vials (1 mg/mL). It should be diluted with 100-250 mL 5% glucose or 0.9% sodium chloride. It is infused over 1-2 hours but can be extended up to 4 hours if reactions occur. A CVAD is not required.

Dose

Tretinoin (ATRA)

45 mg/m²/day will be administered orally in two divided doses (rounded to the nearest 10 mg increment) starting on day 1. Tretinoin (ATRA) treatment should be continued until haematological complete remission or for a maximum of 60 days.

Arsenic Trioxide (ATO)

0.30 mg/kg IV over 2 hours daily for 5 days (days 1-5) in week 1, and thereafter 0.25 mg/kg IV over 2 hours twice a week for an additional 7 weeks.

• If haematologic CR is not achieved by 60 days after start of induction, they should be regarded as resistant and other treatment options considered.

Consolidation: Tretinoin (ATRA)

45 mg/m²/day will be administered orally in two divided doses and rounded to the nearest 10 mg increment. Treatment will be administered for 2 weeks on, followed by 2 weeks off, for a total of 7 cycles (last cycle administered in weeks 25-26).

Arsenic

0.30 mg/kg IV over 2 hours daily for 5 days, in week 1. In weeks 2-4, arsenic will be given on 2 days a week in a dose of 0.25 mg/kg. This is followed by 4 weeks with no treatment. This will be repeated for a total of 4 cycles (last cycle administered in weeks 25-28).

Supportive Care

Side Effects of Arsenic Trioxide

• Arsenic trioxide (ATO) can cause QT prolongation, ventricular arrhythmia, hyperleucocytosis and differentiation (ATRA) syndrome.

  Some patients with APML treated with arsenic trioxide have experienced symptoms similar to a syndrome called the retinoic-acid-acute promyelocytic leukemia (RA-APL) or APML differentiation syndrome, characterized by fever, dyspnoea, weight gain, pulmonary infiltrates and pleural or pericardial effusions, with or without leucocytosis. This syndrome can be fatal. The management of the syndrome has not been fully studied, but high-dose steroids have been used at the first suspicion of the APML differentiation syndrome and appear to mitigate signs and symptoms. At the first signs that could suggest the syndrome (unexplained fever, dyspnoea and/or weight gain, abnormal chest auscultatory findings or radiographic abnormalities), high-dose steroids (dexamethasone 10 mg intravenously BD) should be immediately initiated, irrespective of the leucocyte count, and continued for at least 3 days or longer until signs and symptoms have abated. The majority of patients do not require termination of arsenic trioxide therapy during treatment of the APML differentiation syndrome.

  Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. QT prolongation can lead to a torsade de pointes-type ventricular arrhythmia, which can be fatal. The risk of torsade de pointes is related to the extent of QT prolongation, concomitant administration of QT prolonging drugs, a history of torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalemia or hypomagnesemia.

  if possible, drugs that are known to prolong the QT interval should be discontinued. For QTc greater than 500 msec, corrective measures should be completed and the QTc reassessed with serial ECGs prior to considering using ATO. Patients who reach an absolute QT interval value > 500 msec should be reassessed and immediate action should be taken to correct concomitant risk factors, if any, while the risk/benefit of continuing versus suspending ATO therapy should be considered. If syncope, rapid or irregular heartbeat develops, the patient should be hospitalized for monitoring, serum electrolytes should be assessed, ATO therapy should be temporarily discontinued until the QTc interval regresses to below 460 msec, electrolyte abnormalities are corrected, and the syncope and irregular heartbeat cease.

• Other side effects include:
  • polyneuropathy
  • dry skin
  • light-headedness during the infusion
  • fatigue
  • musculoskeletal pain
  • gastrointestinal disturbance
  • mild hyperglycaemia

  Thrombophlebitis is secondary to the sclerosing effect of arsenic.

• Monitor electrolytes (potassium, calcium, and magnesium) and creatinine and correct before treatment. Keep potassium above 4 mmol/L and magnesium above 0.7 mmol/L.
• Baseline (before treatment). This should be repeated at least weekly and before each treatment if there is concern about the QTc.
• CBC + diff, and coag should be checked twice a week.

This drug will be discontinued in the event of cardiac arrhythmias or severe neurological toxicity.

Anti-fungal Prophylaxis

Azoles should be avoided if treating with arsenic.

Remission Criteria

These are the same as for other forms of AML. However, the distinction between normal and abnormal promyelocytes can be difficult. The PML-RARα defect can persist for some months even though the patient has entered haematological remission. The criteria for morphological complete remission is less than 5% blast cells and no hypergranular promyelocytes.

Molecular remission should be assessed after each course of chemotherapy and then on a 3-monthly basis for 2 years. Marrow samples will be collected at day 60 – following course 1 in patients requiring prolonged tretinoin (ATRA) to achieve CR. Samples will be tested by RQ-PCR for assessment of molecular remission and also sent to the Guys Lab in London by Molecular Biology. It is important to ensure this instruction and the precise details of the stage of treatment are included on the form.

Topic Code: 32080