Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

newly diagnosed AML: suitable for intensive chemotherapy

1st line – intensive induction therapy or clinical trial

Back
ACUTE
|
newly diagnosed AML: suitable for intensive chemotherapy
1st line – 

intensive induction therapy or clinical trial

Induction therapy is the first phase of treatment.

The aim of induction therapy is to achieve complete remission with low or undetectable measurable (minimal) residual disease (MRD). See Criteria for treatment response criteria.

Patients with acute myeloid leukaemia (AML) who are fit and able to tolerate intensive therapy should undergo induction therapy with dose-intense chemotherapy regimens.[27][45]

The standard chemotherapy backbone for intensive induction therapy is cytarabine plus an anthracycline, which is associated with a complete remission rate of 70% to 80% in patients <60 years of age.[72][73][74][75]​ In patients ≥60 years of age, the complete remission rate is lower (60% to 70%).[76][77]​ However, complete remission rate varies significantly depending on disease biology.

Targeted therapies can be added to intensive chemotherapy regimens for patients with certain AML subtypes, biological markers, or genetic abnormalities.[27][45]​​

The recommended treatment approach for patients eligible for intensive induction therapy is premised on European LeukemiaNet (ELN) risk stratification risk groups. The ELN risk stratification is based on genetic abnormalities; other risk factors include therapy-related AML (tAML) or antecedent myelodysplastic syndrome (MDS)/chronic myelomonocytic leukaemia (CMML).[45] See Criteria for European LeukemiaNet risk stratification by genetic abnormalities.

The following regimens are recommended for patients eligible for intensive induction therapy who have favourable-risk disease according to cytogenetic abnormalities (i.e., RUNX1::RUNX1T1 or CBFB::MYH11 associated with core binding factor [CBF]-AML): cytarabine for 7 days plus an anthracycline (e.g., daunorubicin or idarubicin) for 3 days (standard 7+3 [daunorubicin or idarubicin]); cytarabine for 7 days plus mitoxantrone for 3 days (standard 7+3 [mitoxantrone]), for patients ≥60 years of age; standard 7+3 (daunorubicin or idarubicin) plus gemtuzumab ozogamicin, for CD33-positive AML; fludarabine plus cytarabine plus granulocyte colony-stimulating factor (G-CSF) plus idarubicin (i.e., FLAG-IDA) plus gemtuzumab ozogamicin, for CD33-positive AML (use with caution in patients >60 years of age).[45]

The following regimens are recommended for patients eligible for intensive induction therapy who have favourable-risk disease according to genetic mutations (i.e., mutated NPM1 without FLT3-ITD; or basic leucine zipper [bZIP] in-frame mutated CEBPA), or intermediate-risk disease: standard 7+3 (daunorubicin or idarubicin); standard 7+3 (mitoxantrone), for patients ≥60 years of age; FLAG-IDA (use with caution in patients >60 years of age); cladribine plus cytarabine plus G-CSF plus mitoxantrone (CLAG-M); standard 7+3 (daunorubicin or idarubicin) plus gemtuzumab ozogamicin, for CD33-positive AML; FLAG-IDA plus gemtuzumab ozogamicin, for CD33-positive AML (use with caution in patients >60 years of age); standard 7+3 (daunorubicin or idarubicin) plus midostaurin, for FLT3-ITD mutated or FLT3-TKD mutated AML; standard 7+3 (daunorubicin or idarubicin) plus quizartinib, for FLT3-ITD mutated AML only.[45]

The following regimens are recommended for patients eligible for intensive induction therapy who have tAML other than CBF-AML, or antecedent MDS/CMML, or cytogenetic changes consistent with MDS (previously classified as AML with myelodysplasia-related changes [AML-MRC]): liposomal daunorubicin/cytarabine, preferred for patients ≥60 years of age; standard 7+3 (daunorubicin or idarubicin), preferred for patients <60 years of age; a hypomethylating agent (decitabine or azacitidine) plus venetoclax.[45]

A clinical trial (preferred) or the following regimens are recommended for patients eligible for intensive induction therapy who have poor/adverse-risk disease without TP53 mutation or 17p deletion: standard 7+3 (daunorubicin or idarubicin); liposomal daunorubicin/cytarabine; FLAG-IDA (use with caution in patients >60 years of age); a hypomethylating agent (decitabine or azacitidine) plus venetoclax (a lower-intensity therapy); CLAG-M.[45] 

A clinical trial is recommended for patients with TP53 mutation or 17p deletion as these patients respond poorly to standard induction chemotherapy and have an especially poor prognosis.[45][78] If a clinical trial is not available, less intensive therapy (e.g., decitabine plus venetoclax) is preferred.[45][79] 

Patients who achieve complete remission with induction therapy should proceed to consolidation therapy. Those who do not achieve complete remission following induction therapy are considered to have refractory disease.

The long-term treatment goal is to improve disease-free survival and overall survival, with minimal long-term adverse effects. For fit younger patients who are treated with intensive chemotherapy, the overall goal is disease cure.

The goals of treatment should be discussed with the patient in the context of their disease, fitness, and preferences, and this should inform decision-making and treatment planning throughout the course of treatment.

Enrolment in a clinical trial should be considered for all patients, where possible.

MRD assessment (along with standard morphology-based assessment) should be performed during and after treatment to assess treatment response and inform prognosis and treatment planning. The European LeukemiaNet has published recommendations for assessing MRD (including frequency and timing) in AML.​​​​​​​[27][83]

See local specialist protocol for dosing guidelines.

Primary options

Standard 7+3 (daunorubicin or idarubicin)

cytarabine

-- AND --

daunorubicin

or

idarubicin

OR

Standard 7+3 (mitoxantrone)

cytarabine

and

mitoxantrone

OR

Standard 7+3 (daunorubicin or idarubicin) plus gemtuzumab ozogamicin

cytarabine

-- AND --

daunorubicin

or

idarubicin

-- AND --

gemtuzumab ozogamicin

OR

FLAG-IDA plus gemtuzumab ozogamicin

fludarabine

and

cytarabine

and

filgrastim

and

idarubicin

and

gemtuzumab ozogamicin

OR

FLAG-IDA

fludarabine

and

cytarabine

and

filgrastim

and

idarubicin

OR

CLAG-M

cladribine

and

cytarabine

and

filgrastim

and

mitoxantrone

OR

Standard 7+3 (daunorubicin or idarubicin) plus midostaurin

cytarabine

-- AND --

daunorubicin

or

idarubicin

-- AND --

midostaurin

OR

Standard 7+3 (daunorubicin or idarubicin) plus quizartinib

cytarabine

-- AND --

daunorubicin

or

idarubicin

-- AND --

quizartinib

OR

daunorubicin/cytarabine liposomal

OR

decitabine

or

azacitidine

-- AND --

venetoclax

Plus – supportive care

Back
ACUTE
|
newly diagnosed AML: suitable for intensive chemotherapy
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Consider supportive care measures for all patients, at all stages of treatment, to prevent or manage complications.

Patients with acute myeloid leukaemia (AML) who are unsuitable for or decline intensive or lower-intensity therapy should be offered best supportive care.[45][116]​​ 

Electrolyte abnormalities: correction of electrolyte abnormalities is important before and during treatment (particularly for patients treated with venetoclax). Patients should be commenced on hydration (e.g., intravenous fluids).

Tumour lysis syndrome (TLS): an oncological emergency. TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment with chemotherapy. Spontaneous TLS is rare; elevated white blood cell (WBC) count (tumour burden) is a risk factor. TLS can lead to cardiac arrhythmias, seizures, acute kidney injury, and death, if untreated.​ Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricaemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS.​ TLS associated with venetoclax may occur as early as 6-8 hours following the first dose in patients with AML.[96] TLS risk assessment should be carried out before administering venetoclax, and​ guidance on TLS prophylaxis, laboratory monitoring, dose titration, and drug interactions should be strictly adhered to during treatment with venetoclax.[45][96] See Tumour lysis syndrome.

Hyperleukocytosis: generally defined as a WBC count >100 × 10⁹/L (>100,000/microlitre) and is considered a poor prognostic factor. In AML patients, hydroxycarbamide is recommended for leukoreduction.[27][45]​ Lower WBC count to <25 × 10⁹/L (<25,000/microlitre) before initiating treatment (particularly if hypomethylating agents and venetoclax are to be used).[27][45] Urgent leukapheresis may be considered in patients with AML (not including APL) who are symptomatic and have a very high WBC count.[27][45][70]​​[107]​​ 

Anaemia and thrombocytopenia: red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[116] Packed red blood cell transfusion is recommended to keep haematocrit >25%. Platelets should be transfused once platelet count is <10 × 10⁹/L (<10,000/microlitre) or with any signs of bleeding.[27][45]​​ Platelet count needs to be maintained at >50 × 10⁹/L (>50,000/microlitre) in those with significant bleeding.[45][107][117]​​​​ Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalised by infusions of fresh frozen plasma and cryoprecipitate in those with significant bleeding.[45][107]

Infections and febrile neutropenia: during acute illness and chemotherapy, all patients should receive antibiotic prophylaxis (e.g., a fluoroquinolone) to reduce the risk of infection and febrile neutropenia.[118] Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[118]​ Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents. See Febrile neutropenia.

Plus – intrathecal cytarabine and/or methotrexate

Back
ACUTE
|
newly diagnosed AML: suitable for intensive chemotherapy
|
with CNS involvement
Plus – 

intrathecal cytarabine and/or methotrexate

Treatment recommended for ALL patients in selected patient group

Central nervous system (CNS) imaging and diagnostic lumbar puncture should be carried out in patients with neurological signs and symptoms suggesting CNS involvement.[45]

If CNS disease is confirmed on diagnostic lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4-6 weeks.[45]

A screening lumbar puncture (in patients without neurological signs and symptoms) should be considered to detect occult CNS involvement at first remission before first intensive consolidation in patients at high-risk for CNS disease (e.g., patients with acute myeloid leukaemia [AML] with FLT3 mutations).[45]

If occult CNS disease is confirmed on screening lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear.[45]​​​ Alternatively, if the patient is to receive consolidation therapy containing doses of cytarabine that can cross the blood-brain barrier (i.e., ≥2 g/square metre of body surface area), then clearance of CNS disease should be documented on lumbar puncture after the first cycle of consolidation.[45]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

and/or

methotrexate

newly diagnosed AML: not suitable for intensive chemotherapy

1st line – lower-intensity therapy or clinical trial

Back
ACUTE
|
newly diagnosed AML: not suitable for intensive chemotherapy
1st line – 

lower-intensity therapy or clinical trial

Lower-intensity therapy should be considered for newly diagnosed patients who are not suitable for intensive chemotherapy (e.g., due to age, frailty, comorbidities).

The following lower-intensity regimens are recommended for acute myeloid leukaemia (AML) patients with an IDH1 mutation who are ineligible for intensive induction therapy: azacitidine plus venetoclax; azacitidine plus ivosidenib; decitabine plus venetoclax; ivosidenib monotherapy.[45]

The following lower-intensity regimens are recommended for AML patients without an IDH1 mutation who are ineligible for intensive induction therapy: azacitidine plus venetoclax; decitabine plus venetoclax; cladribine plus low-dose cytarabine (LDAC) plus venetoclax.[45]

Other lower-intensity regimens that can be considered for AML patients ineligible for intensive induction therapy include: LDAC plus venetoclax, for those with prior exposure to azacitidine or decitabine; LDAC plus glasdegib; gilteritinib with or without azacitidine, for FLT3-ITD-mutated or FLT3-TKD-mutated AML; enasidenib with or without azacitidine, for IDH2-mutated AML; gemtuzumab ozogamicin, for CD33-positive AML.[45] Decisions relating to prescribing of other lower-intensity regimens will be informed by IDH1 mutation status.

Targeted therapies may be associated with serious complications. Tumour lysis syndrome (TLS) is an oncological emergency that has been uncommonly reported in patients with AML treated with venetoclax.[96] Differentiation syndrome has been reported in patients treated with ivosidenib, enasidenib, and gilteritinib, which can be life-threatening if not treated.[97][98][99][100]​

Patients responding to lower-intensity regimens may continue these regimens until disease progression or intolerance.[27][45][71] 

Allogeneic stem cell transplantation (SCT) may be an option in select patients who respond to lower-intensity therapy.[45] If eligible and a suitable donor is available, patients should undergo allogeneic SCT (with reduced-intensity conditioning) at first remission.[45][70] 

The goals of treatment should be discussed with the patient in the context of their disease, fitness, and preferences, and this should inform decision-making and treatment planning throughout the course of treatment.

In older patients, the treatment goal is usually to achieve complete remission that extends survival and quality of life.

Enrolment in a clinical trial should be considered for all patients, where possible.

Measurable (minimal) residual disease (MRD) assessment (along with standard morphology-based assessment) should be performed during and after treatment to assess treatment response and inform prognosis and treatment planning. The European LeukemiaNet has published recommendations for assessing MRD (including frequency and timing) in AML.[27][83]

See local specialist protocol for dosing guidelines.

Primary options

azacitidine

and

venetoclax

OR

azacitidine

and

ivosidenib

OR

decitabine

and

venetoclax

OR

ivosidenib

OR

cladribine

and

cytarabine

and

venetoclax

OR

cytarabine

and

venetoclax

OR

cytarabine

and

glasdegib

OR

gilteritinib

OR

gilteritinib

and

azacitidine

OR

enasidenib

OR

enasidenib

and

azacitidine

OR

gemtuzumab ozogamicin

Plus – supportive care

Back
ACUTE
|
newly diagnosed AML: not suitable for intensive chemotherapy
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Consider supportive care measures for all patients, at all stages of treatment, to prevent or manage complications.

Patients with acute myeloid leukaemia (AML) who are unsuitable for or decline intensive or lower-intensity therapy should be offered best supportive care.[45][116]

Electrolyte abnormalities: correction of electrolyte abnormalities is important before and during treatment (particularly for patients treated with venetoclax). Patients should be commenced on hydration (e.g., intravenous fluids).

Tumour lysis syndrome (TLS): an oncological emergency. TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment. Spontaneous TLS is rare; elevated white blood cell (WBC) count (tumour burden) is a risk factor. TLS can lead to cardiac arrhythmias, seizures, acute kidney injury, and death, if untreated.​ Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricaemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS. TLS associated with venetoclax may occur as early as 6-8 hours following the first dose in patients with AML.[96]​ TLS risk assessment should be carried out before administering venetoclax, and​ guidance on TLS prophylaxis, laboratory monitoring, dose titration, and drug interactions should be strictly adhered to during treatment with venetoclax.[45][96]​​​ See Tumour lysis syndrome.

Differentiation syndrome: treatments for AML (e.g., ivosidenib, enasidenib, gilteritinib) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[97][98]​​[99][114][115][100]​​ Differentiation syndrome has been reported as early as 10 days, and up to 5 months, after starting enasidenib. Differentiation syndrome is characterised by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC count (>10 × 10⁹/L [>10,000/microlitre]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[107]​ In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[107]

Hyperleukocytosis: generally defined as a WBC count >100 × 10⁹/L (>100,000/microlitre) and is considered a poor prognostic factor. In AML patients, hydroxycarbamide is recommended for leukoreduction.[27][45]​ Lower WBC count to <25 × 10⁹/L (<25,000/microlitre) before initiating treatment (particularly if hypomethylating agents and venetoclax are to be used).[27][45] Urgent leukapheresis may be considered in patients with AML (not including APL) who are symptomatic and have a very high WBC count.[27][45][70]​​​[107]​​ 

Anaemia and thrombocytopenia: red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[116]​ Packed red blood cell transfusion is recommended to keep haematocrit >25%. Platelets should be transfused once platelet count is <10 × 10⁹/L (<10,000/microlitre) or with any signs of bleeding.[27][45]​​​ Platelet count needs to be maintained at >50 × 10⁹/L (>50,000/microlitre) in those with significant bleeding.[45][107][117]​​​​ Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalised by infusions of fresh frozen plasma and cryoprecipitate in those with significant bleeding.[45][107]

Infections and febrile neutropenia: during acute illness and chemotherapy, all patients should receive antibiotic prophylaxis (e.g., a fluoroquinolone) to reduce the risk of infection and febrile neutropenia.[118]​ Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[118] Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents. See Febrile neutropenia.

Plus – intrathecal cytarabine and/or methotrexate

Back
ACUTE
|
newly diagnosed AML: not suitable for intensive chemotherapy
|
with CNS involvement
Plus – 

intrathecal cytarabine and/or methotrexate

Treatment recommended for ALL patients in selected patient group

Central nervous system (CNS) imaging and diagnostic lumbar puncture should be carried out in patients with neurological signs and symptoms suggesting CNS involvement.[45]

If CNS disease is confirmed on diagnostic lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4-6 weeks.[45]​​​​

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

and/or

methotrexate

newly diagnosed non-high-risk acute promyelocytic leukaemia (APL)

1st line – induction therapy

Back
ACUTE
|
newly diagnosed non-high-risk acute promyelocytic leukaemia (APL)
1st line – 

induction therapy

APL is a subtype of acute myeloid leukaemia (AML; characterised by the presence of the PML::RARA fusion gene) that requires urgent treatment to prevent very early death caused by coagulopathy.[45][70][107]

Treatment should commence as soon as APL is suspected (i.e., before confirmation by genetic testing).

Patients with APL are managed in three treatment phases: induction, consolidation, and maintenance.

Treatment is based on whether patients are non-high risk (defined as white blood cell [WBC] count ≤10 × 10⁹/L [≤10,000/microlitre] at presentation) or high risk (defined as WBC count >10 × 10⁹/L [>10,000/microlitre] at presentation).[45][70][107]

Once a treatment regimen and protocol have been decided, it should be adhered to in its entirety from induction to consolidation and maintenance (barring major complication or inadequate response).[45]

Induction regimens for non-high-risk APL include: all-trans-retinoic acid (ATRA; also known as tretinoin) plus arsenic trioxide (standard of care); or ATRA plus idarubicin or gemtuzumab ozogamicin (considered only if arsenic trioxide is not available or contraindicated).[45][107]

Induction therapy should continue until complete remission is achieved, after which consolidation therapy should be given.[45][107] Complete remission following ATRA-based induction therapy is achieved in most (>90%) patients.[108]

ATRA and arsenic trioxide can cause differentiation syndrome, which can be life-threatening if not treated promptly. Arsenic trioxide can also prolong QT interval and cause electrolyte abnormalities.

See local specialist protocol for dosing guidelines.

Primary options

tretinoin

and

arsenic trioxide

Secondary options

tretinoin

and

idarubicin

OR

tretinoin

and

gemtuzumab ozogamicin

Plus – supportive care

Back
ACUTE
|
newly diagnosed non-high-risk acute promyelocytic leukaemia (APL)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Consider supportive care measures for all patients, at all stages of treatment, to prevent or manage complications.

Electrolyte abnormalities: correction of electrolyte abnormalities is important before and during treatment (particularly for patients with APL who are treated with arsenic trioxide). Patients should be commenced on hydration (e.g., intravenous fluids).

Tumour lysis syndrome (TLS): an oncological emergency. TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment. Spontaneous TLS is rare; elevated white blood cell (WBC) count (tumour burden) is a risk factor. TLS can lead to cardiac arrhythmias, seizures, acute kidney injury, and death, if untreated.​ Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricaemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS. See Tumour lysis syndrome.

Differentiation syndrome: treatments for APL (e.g., ATRA, arsenic trioxide) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[99][114][115][100]​ Differentiation syndrome is characterised by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC (>10 × 10⁹/L [>10,000/microlitre]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[107] In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[107]

Hyperleukocytosis: generally defined as a WBC count >100 × 10⁹/L (>100,000/microlitre) and is considered a poor prognostic factor. In APL patients with low-risk disease, hydroxycarbamide should be considered to manage high WBC count during treatment with ATRA and arsenic trioxide (particularly if differentiation syndrome occurs).[45][107]​​​ Leukapheresis is not recommended for patients with APL because it may worsen coagulopathy.[45][70]​​[107]

Anaemia and thrombocytopenia: red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[116]​ During the acute phase of APL, patients are at particular risk of significant coagulopathy. Packed red blood cell transfusion is recommended to keep haematocrit >25%. Platelets should be transfused once platelet count is <10 × 10⁹/L (<10,000/microlitre) or with any signs of bleeding.[27][45]​​​​ Platelet count needs to be maintained at >50 × 10⁹/L (>50,000/microlitre) in patients with APL or those with significant bleeding.[45][107][117]​ Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalised by infusions of fresh frozen plasma and cryoprecipitate in patients with APL or those with significant bleeding.[45][107] 

Infections and febrile neutropenia: during acute illness and chemotherapy, all patients should receive antibiotic prophylaxis (e.g., a fluoroquinolone) to reduce the risk of infection and febrile neutropenia.[118]​ Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[118] Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents. See Febrile neutropenia.

Plus – intrathecal cytarabine and/or methotrexate

Back
ACUTE
|
newly diagnosed non-high-risk acute promyelocytic leukaemia (APL)
|
with CNS involvement
Plus – 

intrathecal cytarabine and/or methotrexate

Treatment recommended for ALL patients in selected patient group

Central nervous system (CNS) imaging and diagnostic lumbar puncture should be carried out in patients with neurological signs and symptoms suggesting CNS involvement.[45]

If CNS disease is confirmed on diagnostic lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4-6 weeks.[45]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

and/or

methotrexate

newly diagnosed high-risk acute promyelocytic leukaemia (APL)

1st line – induction therapy

Back
ACUTE
|
newly diagnosed high-risk acute promyelocytic leukaemia (APL)
1st line – 

induction therapy

APL is a subtype of acute myeloid leukaemia (AML; characterised by the presence of the PML::RARA fusion gene) that requires urgent treatment to prevent very early death caused by coagulopathy.[45][70][107]

Treatment should commence as soon as APL is suspected (i.e., before confirmation by genetic testing).

Patients with APL are managed in three treatment phases: induction, consolidation, and maintenance.

Treatment is based on whether patients are non-high risk (defined as white blood cell [WBC] count ≤10 × 10⁹/L [≤10,000/microlitre] at presentation) or high risk (defined as WBC count >10 × 10⁹/L [>10,000/microlitre] at presentation).[45][70][107]

Once a treatment regimen and protocol have been decided, it should be adhered to in its entirety from induction to consolidation and maintenance (barring major complication or inadequate response).[45]

Induction regimens for high-risk APL include: all-trans-retinoic acid (ATRA; also known as tretinoin) plus arsenic trioxide plus idarubicin; or ATRA plus arsenic trioxide plus gemtuzumab ozogamicin (single dose); or ATRA plus anthracycline-based chemotherapy (e.g., idarubicin; or daunorubicin plus cytarabine).[45][107]

Induction therapy should continue until complete remission is achieved, after which consolidation therapy should be given.[45][107] Complete remission following ATRA-based induction therapy is achieved in most (>90%) patients.[108]​​

ATRA and arsenic trioxide can cause differentiation syndrome, which can be life-threatening if not treated promptly. Arsenic trioxide can also prolong QT interval and cause electrolyte abnormalities.

See local specialist protocol for dosing guidelines.

Primary options

tretinoin

-- AND --

arsenic trioxide

-- AND --

idarubicin

OR

tretinoin

and

arsenic trioxide

and

gemtuzumab ozogamicin

Secondary options

tretinoin

and

idarubicin

OR

tretinoin

and

daunorubicin

and

cytarabine

Plus – supportive care

Back
ACUTE
|
newly diagnosed high-risk acute promyelocytic leukaemia (APL)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Consider supportive care measures for all patients, at all stages of treatment, to prevent or manage complications.

Electrolyte abnormalities: correction of electrolyte abnormalities is important before and during treatment (particularly for patients with APL who are treated with arsenic trioxide). Patients should be commenced on hydration (e.g., intravenous fluids).

Tumour lysis syndrome (TLS): an oncological emergency. TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment. Spontaneous TLS is rare; elevated white blood cell (WBC) count (tumour burden) is a risk factor. TLS can lead to cardiac arrhythmias, seizures, acute kidney injury, and death, if untreated.​ Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricaemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS. See Tumour lysis syndrome.

Differentiation syndrome: treatments for APL (e.g., ATRA, arsenic trioxide) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[99][114][115][100]​ Differentiation syndrome is characterised by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC count (>10 × 10⁹/L [>10,000/microlitre]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[107]​ In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[107]

Hyperleukocytosis: generally defined as a WBC count >100 × 10⁹/L (>100,000/microlitre) and is considered a poor prognostic factor. In APL patients with low-risk disease, hydroxycarbamide should be considered to manage high WBC count during treatment with ATRA and arsenic trioxide (particularly if differentiation syndrome occurs).[45][107]​​​ Leukapheresis is not recommended for patients with APL because it may worsen coagulopathy.[45][70][107]​​

Anaemia and thrombocytopenia: red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[116]​ During the acute phase of APL, patients are at particular risk of significant coagulopathy. Packed red blood cell transfusion is recommended to keep haematocrit >25%. Platelets should be transfused once platelet count is <10 × 10⁹/L (<10,000/microlitre) or with any signs of bleeding.[27][45]​​ Platelet count needs to be maintained at >50 × 10⁹/L (>50,000/microlitre) in patients with APL or those with significant bleeding.[45][107][117]​​​​ Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalised by infusions of fresh frozen plasma and cryoprecipitate in patients with APL or those with significant bleeding.[45][107]​ 

Infections and febrile neutropenia: during acute illness and chemotherapy, all patients should receive antibiotic prophylaxis (e.g., a fluoroquinolone) to reduce the risk of infection and febrile neutropenia.[118] Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[118]​ Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents. See Febrile neutropenia.

Plus – intrathecal cytarabine and/or methotrexate

Back
ACUTE
|
newly diagnosed high-risk acute promyelocytic leukaemia (APL)
|
with CNS involvement
Plus – 

intrathecal cytarabine and/or methotrexate

Treatment recommended for ALL patients in selected patient group

Central nervous system (CNS) imaging and diagnostic lumbar puncture should be carried out in patients with neurological signs and symptoms suggesting CNS involvement.[45]

If CNS disease is confirmed on diagnostic lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4-6 weeks.[45]

A screening lumbar puncture (in patients without neurological signs and symptoms) should be considered to detect occult CNS involvement at first remission before first intensive consolidation in patients at high-risk for CNS disease (e.g., patients with high-risk APL).[45]

If occult CNS disease is confirmed on screening lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear.[45]​​ Alternatively, if the patient is to receive consolidation therapy containing doses of cytarabine that can cross the blood-brain barrier (i.e., ≥2 g/square metre of body surface area), then clearance of CNS disease should be documented on lumbar puncture after the first cycle of consolidation.[45]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

and/or

methotrexate

ONGOING

complete remission: AML

1st line – consolidation therapy

Back
ONGOING
|
complete remission: AML
1st line – 

consolidation therapy

Patients with acute myeloid leukaemia (AML) who achieve complete remission with intensive induction therapy should proceed to consolidation therapy.

Patients responding to lower-intensity regimens may continue these regimens until disease progression or intolerance.[27][45][71] 

The aim of consolidation therapy is to maintain complete remission and reduce the risk of relapse following intensive induction therapy.

Consolidation therapy is guided by risk factors for relapse (e.g., genetic abnormalities, white blood cell (WBC) count at presentation, measurable [minimal] residual disease [MRD]).

Consolidation regimens usually consist of up to 4 cycles of intermediate-dose or high-dose cytarabine (IDAC or HiDAC) alone or in combination with other chemotherapy drugs (e.g., idarubicin, daunorubicin, mitoxantrone) and/or targeted therapy (e.g., gemtuzumab ozogamicin, midostaurin, or quizartinib) if the targeted therapy was used during intensive induction therapy.[27][45]

Patients who received liposomal daunorubicin/cytarabine for intensive induction therapy (e.g., those with therapy-related AML [tAML] other than core binding factor-AML [CBF-AML]) can also receive this regimen for consolidation therapy.[45][80][81][82]

Patients with poor/adverse-risk disease (according to genetic abnormalities) who received the FLAG-IDA regimen or a hypomethylating agent (decitabine or azacitidine) plus venetoclax regimen for induction therapy can receive these regimens for consolidation therapy.[27][45]

MRD assessment (along with standard morphology-based assessment) should be performed during and after treatment to assess treatment response and inform prognosis and treatment planning. MRD should also be assessed at the time of, and following, allogeneic stem cell transplantation.[45] The European LeukemiaNet has published recommendations for assessing MRD (including frequency and timing) in AML.[27][83]​​​​​​​​​​​

See local specialist protocol for regimens and dosing guidelines.

Plus – supportive care

Back
ONGOING
|
complete remission: AML
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Consider supportive care measures for all patients, at all stages of treatment, to prevent or manage complications.

Patients with acute myeloid leukaemia (AML) who are unsuitable for or decline intensive or lower-intensity therapy should be offered best supportive care.[45][116]

Electrolyte abnormalities: correction of electrolyte abnormalities is important before and during treatment (particularly for patients treated with venetoclax). Patients should be commenced on hydration (e.g., intravenous fluids).

Tumour lysis syndrome (TLS): an oncological emergency. TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment. Spontaneous TLS is rare; elevated white blood cell (WBC) count (tumour burden) is a risk factor. TLS can lead to cardiac arrhythmias, seizures, acute kidney injury, and death, if untreated.​ Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricaemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS. TLS associated with venetoclax may occur as early as 6-8 hours following the first dose in patients with AML.[96] TLS risk assessment should be carried out before administering venetoclax, and​ guidance on TLS prophylaxis, laboratory monitoring, dose titration, and drug interactions should be strictly adhered to during treatment with venetoclax.[45][96]​ See Tumour lysis syndrome.

Hyperleukocytosis: generally defined as a WBC count >100 × 10⁹/L (>100,000/microlitre) and is considered a poor prognostic factor. In AML patients, hydroxycarbamide is recommended for leukoreduction.[27][45]​ Lower WBC count to <25 × 10⁹/L (<25,000/microlitre) before initiating treatment (particularly if hypomethylating agents and venetoclax are to be used).[27][45]​ Urgent leukapheresis may be considered in patients with AML (not including APL) who are symptomatic and have a very high WBC count.[27][45][70][107]

Anaemia and thrombocytopenia: red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[116]​ Packed red blood cell transfusion is recommended to keep haematocrit >25%. Platelets should be transfused once platelet count is <10 × 10⁹/L (<10,000/microlitre) or with any signs of bleeding.[27][45]​​ Platelet count needs to be maintained at >50 × 10⁹/L (>50,000/microlitre) in those with significant bleeding.[45][107][117]​​​​​ Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalised by infusions of fresh frozen plasma and cryoprecipitate in those with significant bleeding.[45][107] 

Infections and febrile neutropenia: during acute illness and chemotherapy, all patients should receive antibiotic prophylaxis (e.g., a fluoroquinolone) to reduce the risk of infection and febrile neutropenia.[118] Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[118]​ Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents. See Febrile neutropenia.

Consider – stem cell transplantation

Back
ONGOING
|
complete remission: AML
Consider – 

stem cell transplantation

Additional treatment recommended for SOME patients in selected patient group

Patients with intermediate-risk disease and particularly those with poor/adverse-risk disease (including those with therapy-related AML [tAML] other than core binding factor-AML [CBF-AML], or antecedent myelodysplastic syndrome [MDS]/chronic myelomonocytic leukaemia [CMML], or cytogenetic changes consistent with MDS (previously classified as AML with myelodysplasia-related changes [AML-MRC]) may be considered for allogeneic stem cell transplantation (SCT; with reduced-intensity conditioning for older patients) at first complete remission (i.e., in lieu of consolidation chemotherapy) if they are fit and able to tolerate SCT and a suitable donor is available.[45][84]​​​​​​[85]

Patients with favourable-risk disease may be considered for allogeneic SCT at first complete remission if they are unable to complete consolidation therapy or they have persistent measurable (minimal) residual disease (MRD) and a suitable donor is available.[27][45]

Autologous SCT is not commonly performed, but may be an alternative to allogeneic SCT in select patients (e.g. those with intermediate-risk disease who are MRD negative) if a donor is not available.[27][70][86][87]

Plus – intrathecal cytarabine and/or methotrexate

Back
ONGOING
|
complete remission: AML
|
with CNS involvement
Plus – 

intrathecal cytarabine and/or methotrexate

Treatment recommended for ALL patients in selected patient group

Central nervous system (CNS) imaging and diagnostic lumbar puncture should be carried out in patients with neurological signs and symptoms suggesting CNS involvement.[45]

If CNS disease is confirmed on diagnostic lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4-6 weeks.[45]

A screening lumbar puncture (in patients without neurological signs and symptoms) should be considered to detect occult CNS involvement at first remission before first intensive consolidation in patients at high-risk for CNS disease (e.g., patients with acute myeloid leukaemia [AML] with FLT3 mutations).[45]

If occult CNS disease is confirmed on screening lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear.[45] Alternatively, if the patient is to receive consolidation therapy containing doses of cytarabine that can cross the blood-brain barrier (i.e., ≥2 g/square metre of body surface area), then clearance of CNS disease should be documented on lumbar puncture after the first cycle of consolidation.​​​​[45]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

and/or

methotrexate

Consider – maintenance therapy

Back
ONGOING
|
complete remission: AML
|
eligible for maintenance therapy
Consider – 

maintenance therapy

Additional treatment recommended for SOME patients in selected patient group

Maintenance therapy may be considered after intensive induction/consolidation chemotherapy or allogeneic stem cell transplantation (SCT) in patients with certain AML subtypes, genetic mutations, and high-risk features.

Patients with non-core binding factor AML (non-CBF-AML) who are in complete remission after intensive induction chemotherapy may be considered for oral azacitidine maintenance therapy (until progression or unacceptable toxicity) if no consolidation therapy or some consolidation therapy has been completed and no allogeneic SCT is planned.[45][88]​ Oral azacitidine maintenance therapy should not replace consolidation therapy.

Patients with FLT3-mutated AML who previously received midostaurin or quizartinib (in combination with standard intensive induction and consolidation chemotherapy) may continue these agents as monotherapy post-consolidation chemotherapy if no allogeneic SCT is planned.[45][89][90][91]

Several oral kinase inhibitors can be considered for maintenance therapy in patients with FLT3-mutated AML who are in complete remission post-allogeneic SCT. These include: gilteritinib (FLT3-ITD-mutated or FLT3-TKD-mutated); sorafenib (FLT3-ITD-mutated only); midostaurin (FLT3-ITD-mutated or FLT3-TKD-mutated); and quizartinib (FLT3-ITD-mutated only).[45][90][91]​​​​​[92][93][94]

Gilteritinib is preferred for post-allogeneic SCT maintenance therapy in patients with FLT3-ITD-mutated AML who were measurable (minimal) residual disease (MRD)-positive at first complete remission before transplant.[45] 

Patients with AML with high-risk features (e.g., poor/adverse-risk genetic abnormalities, secondary AML) who are in complete remission post-allogeneic SCT may be considered for maintenance therapy with low-dose decitabine plus granulocyte colony-stimulating factor (G-CSF).[45][119]

The role of maintenance therapy in the post-transplant setting is still evolving.

See local specialist protocol for dosing guidelines.

Primary options

azacitidine

OR

midostaurin

OR

quizartinib

OR

gilteritinib

OR

sorafenib

OR

decitabine

and

filgrastim

complete remission: acute promyelocytic leukaemia (APL)

1st line – consolidation therapy

Back
ONGOING
|
complete remission: acute promyelocytic leukaemia (APL)
1st line – 

consolidation therapy

Consolidation regimens for APL are usually similar to induction regimens (e.g., all-trans-retinoic acid [ATRA; also known as tretinoin] plus arsenic trioxide [for non-high-risk APL]; ATRA plus arsenic trioxide plus chemotherapy [for high-risk APL]).[45]​​[107]

Measurable (minimal) residual disease (MRD) assessment (PCR testing to detect the PML::RARA fusion transcript) should be carried out following consolidation therapy to evaluate treatment response and guide subsequent treatment.​[70][107]​ Patients with high-risk APL should undergo long-term MRD monitoring (e.g., every 3 months for 2 years following treatment) due to the increased risk of relapse.[45][70][107]​ Long-term MRD monitoring is not required for non-high-risk patients in molecular remission following consolidation therapy.

See local specialist protocol for regimens and dosing guidelines.

Plus – supportive care

Back
ONGOING
|
complete remission: acute promyelocytic leukaemia (APL)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Consider supportive care measures for all patients, at all stages of treatment, to prevent or manage complications.

Electrolyte abnormalities: correction of electrolyte abnormalities is important before and during treatment (particularly for patients with APL who are treated with arsenic trioxide). Patients should be commenced on hydration (e.g., intravenous fluids).

Tumour lysis syndrome (TLS): an oncological emergency. TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment. Spontaneous TLS is rare; elevated white blood cell (WBC) count (tumour burden) is a risk factor. TLS can lead to cardiac arrhythmias, seizures, acute kidney injury, and death, if untreated.​ Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS. See Tumour lysis syndrome.

Differentiation syndrome: treatments for APL (e.g., ATRA, arsenic trioxide) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[99][114][115][100]​​ Differentiation syndrome is characterised by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC (>10 × 10⁹/L [>10,000/microlitre]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[107]​ In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[107]

Hyperleukocytosis: generally defined as a WBC count >100 × 10⁹/L (>100,000/microlitre) and is considered a poor prognostic factor. In APL patients with low-risk disease, hydroxycarbamide should be considered to manage high WBC count during treatment with ATRA and arsenic trioxide (particularly if differentiation syndrome occurs).[45][107]​​ Leukapheresis is not recommended for patients with APL because it may worsen coagulopathy.[45][70]​​[107]

Anaemia and thrombocytopenia: red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[116]​ During the acute phase of APL, patients are at particular risk of significant coagulopathy. Packed red blood cell transfusion is recommended to keep haematocrit >25%. Platelets should be transfused once platelet count is <10 × 10⁹/L (<10,000/microlitre) or with any signs of bleeding.[27][45]​​ Platelet count needs to be maintained at >50 × 10⁹/L (>50,000/microlitre) in patients with APL or those with significant bleeding.[45][107][117] Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalised by infusions of fresh frozen plasma and cryoprecipitate in patients with APL or those with significant bleeding.[45][107] 

Infections and febrile neutropenia: during acute illness and chemotherapy, all patients should receive antibiotic prophylaxis (e.g., a fluoroquinolone) to reduce the risk of infection and febrile neutropenia.[118] Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[118] Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents. See Febrile neutropenia.

Plus – intrathecal cytarabine and/or methotrexate

Back
ONGOING
|
complete remission: acute promyelocytic leukaemia (APL)
|
with CNS involvement
Plus – 

intrathecal cytarabine and/or methotrexate

Treatment recommended for ALL patients in selected patient group

Central nervous system (CNS) imaging and diagnostic lumbar puncture should be carried out in patients with neurological signs and symptoms suggesting CNS involvement.[45]​​

If CNS disease is confirmed on diagnostic lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4-6 weeks.[45] 

A screening lumbar puncture (in patients without neurological signs and symptoms) should be considered to detect occult CNS involvement at first remission before first intensive consolidation in patients at high-risk for CNS disease (e.g., patients with high-risk APL).[45] 

If occult CNS disease is confirmed on screening lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear.[45] Alternatively, if the patient is to receive consolidation therapy containing doses of cytarabine that can cross the blood-brain barrier (i.e., ≥2 g/square metre of body surface area), then clearance of CNS disease should be documented on lumbar puncture after the first cycle of consolidation.[45]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

and/or

methotrexate

Consider – maintenance therapy

Back
ONGOING
|
complete remission: acute promyelocytic leukaemia (APL)
|
with high-risk APL
Consider – 

maintenance therapy

Additional treatment recommended for SOME patients in selected patient group

Maintenance therapy may be considered for patients with high-risk APL who achieve molecular remission after consolidation therapy, but it is not required for non-high-risk patients.[70][107]

Maintenance regimens for APL vary depending on the treatment protocol, but usually consist of ATRA plus mercaptopurine and methotrexate for 1-2 years.[109][110][111]

With close measurable (minimal) residual disease (MRD) monitoring post-consolidation, the role of maintenance therapy is now being challenged.[112][113][108]​ In some countries, such as the UK, maintenance therapy for APL is no longer used.

See local specialist protocol for dosing guidelines.

Primary options

tretinoin

and

mercaptopurine

and

methotrexate

relapsed or refractory AML

1st line – salvage therapy ± stem cell transplantation; reinduction therapy; or clinical trial

Back
ONGOING
|
relapsed or refractory AML
1st line – 

salvage therapy ± stem cell transplantation; reinduction therapy; or clinical trial

Patients with relapsed or refractory acute myeloid leukaemia (AML) have a poor prognosis.[101]

There is no standard salvage regimen for relapsed or refractory AML. Where possible, patients should be offered enrolment in a clinical trial.

At relapse, all patients should undergo molecular re-evaluation to identify targets (actionable genes) for salvage therapy, which may have emerged since diagnosis (due to clonal evolution) or were not detected at diagnosis.[27][45]

Important predictors of response to salvage therapy are age, genetic abnormalities, duration of first remission, and history of previous stem cell transplantation (SCT).[102][103]​​[104]

Relapse after first complete remission occurs in approximately 50% of patients who received intensive induction therapy, usually in the first year following treatment.[105] Approximately 40% to 60% of relapsed patients achieve a second complete remission with intensive salvage chemotherapy (e.g., intermediate-dose cytarabine [IDAC] or high-dose cytarabine [HiDAC] with or without an anthracycline or mitoxantrone), although duration of remission is usually limited.[105][102]​​​​[106]​​

Patients who achieve a second complete remission with intensive salvage therapy should be considered for allogeneic SCT (if eligible and a suitable donor is available) to reduce the risk of relapse.[45][70][101]​​

Patients unsuitable for intensive salvage chemotherapy can be considered for lower-intensity salvage therapy, which should be followed by allogeneic SCT (if eligible and a suitable donor is available) or continued until disease progression or intolerance. Options include: venetoclax plus a hypomethylating agent (azacitidine or decitabine) or low-dose subcutaneous cytarabine (LDAC); gilteritinib for patients with FLT3-ITD-mutated or FLT3-TKD-mutated AML; ivosidenib for patients with IDH1-mutated AML (off-label use in Europe); olutasidenib for patients with IDH1-mutated AML; enasidenib for patients with IDH2-mutated AML; gemtuzumab ozogamicin for patients with CD33-positive AML; and revumenib for KMT2A-rearranged AML.​[45]

Patients who are unable to tolerate intensive or lower-intensity salvage therapy or who decline further treatment should be offered best supportive care and/or palliative care.[45]

Reinduction therapy (with chemotherapy) may be considered for patients with relapse following long remission (i.e., ≥12 months) after intensive chemotherapy.[45][70]​​​​​

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

OR

cytarabine

-- AND --

daunorubicin

or

idarubicin

or

mitoxantrone

OR

venetoclax

-- AND --

azacitidine

or

decitabine

or

cytarabine

OR

gilteritinib

OR

ivosidenib

OR

olutasidenib

OR

enasidenib

OR

gemtuzumab ozogamicin

OR

revumenib

Plus – supportive care

Back
ONGOING
|
relapsed or refractory AML
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Consider supportive care measures for all patients, at all stages of treatment, to prevent or manage complications.

Patients with acute myeloid leukaemia (AML) who are unsuitable for or decline intensive or lower-intensity therapy should be offered best supportive care.[45][116]​​ 

Electrolyte abnormalities: correction of electrolyte abnormalities is important before and during treatment (particularly for patients treated with venetoclax). Patients should be commenced on hydration (e.g., intravenous fluids).

Tumour lysis syndrome (TLS): an oncological emergency. TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment. Spontaneous TLS is rare; elevated white blood cell (WBC) count (tumour burden) is a risk factor. TLS can lead to cardiac arrhythmias, seizures, acute kidney injury, and death, if untreated.​ Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricaemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS. TLS associated with venetoclax may occur as early as 6-8 hours following the first dose in patients with AML.[96] TLS risk assessment should be carried out before administering venetoclax, and​ guidance on TLS prophylaxis, laboratory monitoring, dose titration, and drug interactions should be strictly adhered to during treatment with venetoclax.[45][96]​​​​ See Tumour lysis syndrome.

Differentiation syndrome: treatments for AML (e.g., ivosidenib, enasidenib, olutasidenib, gilteritinib) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[99][114][115][100]​​​ Differentiation syndrome has been reported as early as 10 days, and up to 5 months, after starting enasidenib. Differentiation syndrome is characterised by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC count (>10 × 10⁹/L [>10,000/microlitre]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[107] In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[107]

Hyperleukocytosis: generally defined as a WBC count >100 × 10⁹/L (>100,000/microlitre) and is considered a poor prognostic factor. In AML patients, hydroxycarbamide is recommended for leukoreduction.[27][45] Lower WBC count to <25 × 10⁹/L (<25,000/microlitre) before initiating treatment (particularly if hypomethylating agents and venetoclax are to be used).[27][45]​​ Urgent leukapheresis may be considered in patients with AML (not including APL) who are symptomatic and have a very high WBC count.[27][45][70]​​[107]​ 

Anaemia and thrombocytopenia: red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[116]​ Packed red blood cell transfusion is recommended to keep haematocrit >25%. Platelets should be transfused once platelet count is <10 × 10⁹/L (<10,000/microlitre) or with any signs of bleeding.[27][45]​ Platelet count needs to be maintained at >50 × 10⁹/L (>50,000/microlitre) in those with significant bleeding.[45][117][107]​ Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalised by infusions of fresh frozen plasma and cryoprecipitate in those with significant bleeding.[45][107]

Infections and febrile neutropenia: during acute illness and chemotherapy, all patients should receive antibiotic prophylaxis (e.g., a fluoroquinolone) to reduce the risk of infection and febrile neutropenia.[118] Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[118]​ Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents. See Febrile neutropenia.

Plus – intrathecal cytarabine and/or methotrexate

Back
ONGOING
|
relapsed or refractory AML
|
with CNS involvement
Plus – 

intrathecal cytarabine and/or methotrexate

Treatment recommended for ALL patients in selected patient group

Central nervous system (CNS) imaging and diagnostic lumbar puncture should be carried out in patients with neurological signs and symptoms suggesting CNS involvement.[45]

If CNS disease is confirmed on diagnostic lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4-6 weeks.[45]​​

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

and/or

methotrexate

relapsed or refractory acute promyelocytic leukaemia (APL)

1st line – salvage therapy + stem cell transplantation; or clinical trial

Back
ONGOING
|
relapsed or refractory acute promyelocytic leukaemia (APL)
1st line – 

salvage therapy + stem cell transplantation; or clinical trial

Patients with relapsed or refractory APL should be considered for salvage therapy to achieve molecular remission (i.e., measurable [minimal] residual disease [MRD] negativity).

Salvage therapy for relapsed APL should be based on previous treatment and whether relapse occurs early or late (definitions vary, but most relapses occur <2 years).[45][70][107]​​

Patients who relapse early following treatment comprising all-trans-retinoic acid (ATRA; also known as tretinoin) plus arsenic trioxide can be treated with ATRA plus chemotherapy, or single-agent gemtuzumab ozogamicin.[45][107]​

Patients who relapse early following treatment with ATRA plus chemotherapy (without arsenic trioxide) can be treated with arsenic trioxide-containing regimens (e.g., ATRA plus arsenic trioxide).[45][107]​​

Retreatment with the previous regimen may be considered if relapse occurs late.

Patients with relapsed or refractory disease should be referred to a stem cell transplantation (SCT) centre. An autologous SCT should be arranged if remission and MRD negativity are achieved after salvage therapy.[45][107] An allogeneic SCT should be arranged if there is no remission (i.e., refractory disease) or there is detectable MRD after salvage therapy.[45][107]

Patients not eligible for SCT may be continued on salvage therapy or enrolled in a clinical trial (if available).

See local specialist protocol for dosing guidelines.

Primary options

tretinoin

and

idarubicin

OR

tretinoin

and

daunorubicin

and

cytarabine

OR

gemtuzumab ozogamicin

OR

tretinoin

and

arsenic trioxide

OR

tretinoin

-- AND --

arsenic trioxide

-- AND --

idarubicin

or

daunorubicin

OR

tretinoin

and

arsenic trioxide

and

gemtuzumab ozogamicin

Plus – supportive care

Back
ONGOING
|
relapsed or refractory acute promyelocytic leukaemia (APL)
Plus – 

supportive care

Treatment recommended for ALL patients in selected patient group

Consider supportive care measures for all patients, at all stages of treatment, to prevent or manage complications.

Electrolyte abnormalities: correction of electrolyte abnormalities is important before and during treatment (particularly for patients with APL who are treated with arsenic trioxide). Patients should be commenced on hydration (e.g., intravenous fluids).

Tumour lysis syndrome (TLS): an oncological emergency. TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment. Spontaneous TLS is rare; elevated white blood cell (WBC) count (tumour burden) is a risk factor. TLS can lead to cardiac arrhythmias, seizures, acute kidney injury, and death, if untreated.​ Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricaemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS. See Tumour lysis syndrome.

Differentiation syndrome: treatments for APL (e.g., ATRA, arsenic trioxide) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[99][114][115][100] Differentiation syndrome is characterised by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC count (>10 × 10⁹/L [>10,000/microlitre]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[107]​ In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[107]

Hyperleukocytosis: generally defined as a WBC count >100 × 10⁹/L (>100,000/microlitre) and is considered a poor prognostic factor. In APL patients with low-risk disease, hydroxycarbamide should be considered to manage high WBC count during treatment with ATRA and arsenic trioxide (particularly if differentiation syndrome occurs).[45][107]​ Leukapheresis is not recommended for patients with APL because it may worsen coagulopathy.[45][70]​​[107]​ 

Anaemia and thrombocytopenia: red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[116]​ During the acute phase of APL, patients are at particular risk of significant coagulopathy. Packed red blood cell transfusion is recommended to keep haematocrit >25%. Platelets should be transfused once platelet count is <10 × 10⁹/L (<10,000/microlitre) or with any signs of bleeding.[27][45]​ Platelet count needs to be maintained at >50 × 10⁹/L (>50,000/microlitre) in patients with APL or those with significant bleeding.[45][107][117]​​ Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalised by infusions of fresh frozen plasma and cryoprecipitate in patients with APL or those with significant bleeding.[45][107]

Infections and febrile neutropenia: during acute illness and chemotherapy, all patients should receive antibiotic prophylaxis (e.g., a fluoroquinolone) to reduce the risk of infection and febrile neutropenia.[118]​ Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[118] Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents. See Febrile neutropenia.

Plus – intrathecal cytarabine and/or methotrexate

Back
ONGOING
|
relapsed or refractory acute promyelocytic leukaemia (APL)
|
with CNS involvement
Plus – 

intrathecal cytarabine and/or methotrexate

Treatment recommended for ALL patients in selected patient group

Central nervous system (CNS) imaging and diagnostic lumbar puncture should be carried out in patients with neurological signs and symptoms suggesting CNS involvement.[45]

If CNS disease is confirmed on diagnostic lumbar puncture, intrathecal cytarabine or intrathecal methotrexate (or a combination of these drugs) should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4-6 weeks.[45]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

and/or

methotrexate

back arrow

Choose a patient group to see our recommendations

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

Use of this content is subject to our disclaimer