Acute myeloid leukemia

with CD33-positive AML

Back

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 AML who are unsuitable for or decline standard- or low-intensive chemotherapy should be offered best supportive care.[38][126]

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

Hyperleukocytosis: generally defined as a WBC count >100,000/microliter (>100 × 10⁹/L) and is considered a poor prognostic factor. In AML patients, hydroxyurea is recommended for leukoreduction.[23][38] It is recommended that WBC count is lowered to <25,000/microliter (<25 × 10⁹/L). Urgent leukapheresis may be considered in patients with AML (not including APL) who are symptomatic and have a very high WBC count.[38][61]

Anemia and thrombocytopenia: red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[126] Packed red blood cell transfusion is recommended to keep hematocrit >25%. Platelets should be prophylactically transfused once platelet count is <10,000/microliter (<10 × 10⁹/L).[23][38] Platelet count needs to be maintained at >50,000/microliter (>50 × 10⁹/L) in those with significant bleeding.[38][61] Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalized by infusions of fresh frozen plasma and cryoprecipitate in those with significant bleeding.

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.[129] Patients should also receive antifungal prophylaxis with a mold-active antifungal agent (e.g., posaconazole).[129] Patients presenting with febrile illness need to be investigated and treated appropriately and promptly with antibiotics or anti-infective agents. See Febrile neutropenia.

Plus – gemtuzumab ozogamicin

Back

Plus –

gemtuzumab ozogamicin

Treatment recommended for ALL patients in selected patient group

Patients with CD33-positive AML and favorable- or intermediate-risk disease can be treated with gemtuzumab ozogamicin (an anti-CD33 monoclonal antibody conjugated with the cytotoxic agent calicheamicin) in combination with induction and consolidation chemotherapy.[80][81][82][83]

Important adverse effects associated with gemtuzumab ozogamicin include hypersensitivity reactions, hepatotoxicity (veno-occlusive disease), and myelotoxicity.

See local specialist protocol for dosing guidelines.

Primary options

gemtuzumab ozogamicin

with FLT3-mutant AML

Plus – midostaurin or quizartinib

Back

Plus –

midostaurin or quizartinib

Treatment recommended for ALL patients in selected patient group

Patients with FLT3-mutated AML can be treated with the oral tyrosine kinase inhibitors midostaurin (for FLT3-ITD-mutated or FLT3-TKD-mutated) or quizartinib (for FLT3-ITD-mutated only) in combination with standard intensive induction and consolidation chemotherapy.[84][85][86]

Quizartinib is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program.

See local specialist protocol for dosing guidelines.

Primary options

midostaurin

quizartinib

1st line – low-intensity therapy

Back

Plus –

intrathecal cytarabine or methotrexate

Treatment recommended for ALL patients in selected patient group

CNS imaging and lumbar puncture should be carried out in patients with neurologic signs and symptoms suggesting CNS involvement.[38]

A screening lumbar puncture (in patients without neurologic signs and symptoms) should be considered at first remission (before consolidation) in patients at high-risk for CNS disease (e.g., those with white blood cell [WBC] count >40,000/microliter [>40 × 10⁹/L], monocytic lineage, mixed-phenotype acute leukemia, extramedullary disease, or FLT3 mutations).[38]

If CNS disease is confirmed, intrathecal cytarabine or methotrexate should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4 to 6 weeks.[38]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

methotrexate

newly diagnosed AML: not suitable for intensive chemotherapy

Back

1st line –

low-intensity therapy

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

Options include: venetoclax; glasdegib; ivosidenib; enasidenib; and gemtuzumab ozogamicin.

Venetoclax (a BCL-2 inhibitor) is approved for use in combination with a hypomethylating agent (decitabine or azacitidine) or low-dose subcutaneous cytarabine (LDAraC) for patients with newly diagnosed AML ages 75 years or older, or who are unsuitable for intensive induction chemotherapy due to comorbidities.[91][92][93][94][95] Tumor lysis syndrome (TLS) has been uncommonly reported in patients with AML treated with venetoclax.[96]

Glasdegib (a Hedgehog pathway inhibitor) is approved for use in combination with LDAraC for patients ages 75 years or older who are unsuitable for standard induction chemotherapy.[97][98][99]

Ivosidenib (an IDH1 inhibitor) is approved in the US for use as monotherapy or in combination with azacitidine for patients with newly diagnosed IDH1-mutated AML who are ages 75 years or older, or who are unsuitable for intensive induction chemotherapy due to comorbidities.[100][101] Life-threatening differentiation syndrome has been reported in patients receiving ivosidenib.

Enasidenib (an IDH2 inhibitor) may be used as monotherapy or in combination with azacitidine for patients with newly diagnosed IDH2-mutated AML who are unsuitable for intensive induction chemotherapy.[102][103][104] The US Food and Drug Administration (FDA) has issued a warning regarding differentiation syndrome associated with enasidenib.[105] Differentiation syndrome has reportedly occurred as early as 10 days and up to 5 months after starting treatment.

Gemtuzumab ozogamicin (single agent) may be used for patients with CD33-positive AML who are not suitable for standard induction chemotherapy.[106]

Patients should continue low-intensity therapy until disease progression or intolerance.

Stem cell transplantation (SCT) may be an option in select patients who respond to low-intensity therapy. If eligible and a suitable donor is available, patients should undergo allogeneic SCT (with reduced-intensity conditioning) at first remission.[38][60]

Patients with TP53 mutations or 17p deletion are typically unresponsive to standard intensive chemotherapy and the prognosis is poor.[107] A clinical trial is recommended for these patients.[38] If a clinical trial is not available, low-intensity therapy (e.g., venetoclax plus decitabine) and allogeneic SCT (if eligible and a suitable donor is available) can be considered.[95]

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

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

Measurable (minimal) residual disease (MRD) 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.[23][75]

See local specialist protocol for dosing guidelines.

Primary options

venetoclax

-- AND --

decitabine

azacitidine

cytarabine

glasdegib

and

cytarabine

ivosidenib

and

azacitidine

enasidenib

and

azacitidine

gemtuzumab ozogamicin

Back

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 AML who are unsuitable for or decline standard- or low-intensive chemotherapy should be offered best supportive care.[38][126]

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

Tumor lysis syndrome (TLS): an oncologic emergency. TLS is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and/or elevated serum lactate dehydrogenase, which can occur following treatment or spontaneously (rare), particularly if white blood cell (WBC) count (tumor burden) is high. TLS can lead to cardiac arrhythmias, seizures, acute renal failure, 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. TLS associated with venetoclax may occur as early as 6 to 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.[38][96] See Tumor lysis syndrome.

Differentiation syndrome: treatments for AML (e.g., ivosidenib, enasidenib) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[105][115][127][128] Differentiation syndrome is characterized by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC count (>10,000/microliter [>10 × 10⁹/L]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[61] In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[61]

Hyperleukocytosis: generally defined as a WBC count >100,000/microliter (>100 × 10⁹/L) and is considered a poor prognostic factor. In AML patients, hydroxyurea is recommended for leukoreduction.[23][38] It is recommended that WBC count is lowered to <25,000/microliter (<25 × 10⁹/L), particularly before initiating treatment with hypomethylating agents and venetoclax.[23][38] Urgent leukapheresis may be considered in patients with AML (not including APL) who are symptomatic and have a very high WBC count.[38][61]

1st line – induction therapy

Back

Plus –

intrathecal cytarabine or methotrexate

Treatment recommended for ALL patients in selected patient group

CNS imaging and lumbar puncture should be carried out in patients with neurologic signs and symptoms suggesting CNS involvement.[38]

If CNS disease is confirmed, intrathecal cytarabine or methotrexate should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4 to 6 weeks.[38]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

methotrexate

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

Back

1st line –

induction therapy

APL is a subtype of AML (characterized by the presence of the PML::RARA fusion gene) that requires urgent treatment to prevent very early death caused by coagulopathy.[38][60][61]

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 ≤10,000/microliter [≤10 × 10⁹/L] at presentation) or high risk (defined as WBC count >10,000/microliter [>10 × 10⁹/L] at presentation).[38][60][61]

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).[38]

Induction regimens for non-high-risk APL include:[38][61]

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.

Induction therapy should continue until complete remission is achieved, after which consolidation therapy should be given.[61] Complete remission following ATRA-based induction therapy is achieved in most (>90%) patients.[120]

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

tretinoin

and

gemtuzumab ozogamicin

Back

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).

Differentiation syndrome: treatments for APL (e.g., ATRA, arsenic trioxide) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[105][115][127][128] Differentiation syndrome is characterized by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC (>10,000/microliter [>10 × 10⁹/L]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[61] In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[61]

Hyperleukocytosis: generally defined as a WBC count >100,000/microliter (>100 × 10⁹/L) and is considered a poor prognostic factor. In APL patients, hydroxyurea should be considered to manage high WBC count during treatment with ATRA and arsenic trioxide (particularly if differentiation syndrome occurs).[38][61] Leukapheresis is not recommended for patients with APL because it may worsen coagulopathy.[38][61]

Anemia and thrombocytopenia: red blood cell and platelet transfusions may be required depending on symptoms and blood counts.[126] During the acute phase of APL, patients are at particular risk of significant coagulopathy. Packed red blood cell transfusion is recommended to keep hematocrit >25%. Platelets should be prophylactically transfused once platelet count is <10,000/microliter (<10 × 10⁹/L).[23][38] Platelet count needs to be maintained at >50,000/microliter (>50 × 10⁹/L) in patients with APL or those with significant bleeding.[38][61] Activated partial thromboplastin time (aPTT) and fibrinogen levels should be normalized by infusions of fresh frozen plasma and cryoprecipitate in patients with APL or those with significant bleeding.

1st line – induction therapy

Back

Plus –

intrathecal cytarabine or methotrexate

Treatment recommended for ALL patients in selected patient group

CNS imaging and lumbar puncture should be carried out in patients with neurologic signs and symptoms suggesting CNS involvement.[38]

If CNS disease is confirmed, intrathecal cytarabine or methotrexate should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4 to 6 weeks.[38]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

methotrexate

newly diagnosed high-risk acute promyelocytic leukemia (APL)

Back

1st line –

induction therapy

APL is a subtype of AML (characterized by the presence of the PML::RARA fusion gene) that requires urgent treatment to prevent very early death caused by coagulopathy.[38][60][61]

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.

Induction regimens for high-risk APL include:[38][61]

All-trans-retinoic acid (ATRA; also known as tretinoin) plus arsenic trioxide plus an anthracycline (idarubicin or daunorubicin); or

ATRA plus arsenic trioxide plus gemtuzumab ozogamicin (single dose); or

ATRA plus anthracycline-based chemotherapy (e.g., idarubicin; or daunorubicin plus cytarabine).

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

daunorubicin

tretinoin

and

arsenic trioxide

and

gemtuzumab ozogamicin

Secondary options

tretinoin

and

idarubicin

tretinoin

and

daunorubicin

and

cytarabine

Back

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.

Differentiation syndrome: treatments for APL (e.g., ATRA, arsenic trioxide) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[105][115][127][128] Differentiation syndrome is characterized by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC count (>10,000/microliter [>10 × 10⁹/L]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[61] In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[61]

1st line – consolidation therapy

Back

Plus –

intrathecal cytarabine or methotrexate

Treatment recommended for ALL patients in selected patient group

CNS imaging and lumbar puncture should be carried out in patients with neurologic signs and symptoms suggesting CNS involvement.[38]

If CNS disease is confirmed, intrathecal cytarabine or methotrexate should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4 to 6 weeks.[38]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

methotrexate

ONGOING

complete remission: AML

Back

1st line –

consolidation therapy

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

Consolidation therapy is guided by risk factors for relapse (e.g., genetic abnormalities, white blood cell 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).[38]

Patients with therapy-related AML (tAML) or AML with myelodysplasia-related changes (AML-MRC) who received liposomal daunorubicin/cytarabine (also known as CPX-351) for induction therapy can also receive this regimen for consolidation therapy (up to 2 cycles).[72][73][74]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

-- AND --

idarubicin

daunorubicin

mitoxantrone

daunorubicin/cytarabine liposomal

Consider – stem cell transplantation

Back

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 AML who are unsuitable for or decline standard- or low-intensive chemotherapy should be offered best supportive care.[38][126]

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

Back

Consider –

stem cell transplantation

Treatment recommended for SOME patients in selected patient group

Patients with intermediate-risk disease and particularly those with adverse-risk disease may be considered for allogeneic stem cell transplantation (SCT; with reduced-intensity conditioning for older patients) following one or more cycles of consolidation chemotherapy, if they are fit and able to tolerate SCT.[38][76][77] These patients may also proceed directly to transplant if a suitable donor is available at first complete remission (i.e., in lieu of consolidation chemotherapy).

Allogeneic SCT may be considered in patients with favorable-risk disease with persistent MRD if a suitable donor is available.[23][38]

Autologous SCT is 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, but is not commonly performed.[23][60][78][79]

with CD33-positive AML

Plus – gemtuzumab ozogamicin

Back

Plus –

gemtuzumab ozogamicin

Treatment recommended for ALL patients in selected patient group

Important adverse effects associated with gemtuzumab ozogamicin include hypersensitivity reactions, hepatotoxicity (veno-occlusive disease), and myelotoxicity.

See local specialist protocol for dosing guidelines.

Primary options

gemtuzumab ozogamicin

with FLT3-mutant AML

Plus – midostaurin or quizartinib

Back

Plus –

midostaurin or quizartinib

Treatment recommended for ALL patients in selected patient group

Quizartinib is available only through a restricted Risk Evaluation and Mitigation Strategy (REMS) program.

See local specialist protocol for dosing guidelines.

Primary options

midostaurin

quizartinib

eligible for maintenance therapy

Back

Plus –

intrathecal cytarabine or methotrexate

Treatment recommended for ALL patients in selected patient group

CNS imaging and lumbar puncture should be carried out in patients with neurologic signs and symptoms suggesting CNS involvement.[38]

If CNS disease is confirmed, intrathecal cytarabine or methotrexate should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4 to 6 weeks.[38]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

methotrexate

Consider – maintenance therapy

Back

Consider –

maintenance therapy

Treatment recommended for SOME patients in selected patient group

Maintenance therapy with oral azacitidine (single agent) may be considered for patients with complete remission after intensive induction chemotherapy (with or without complete blood count recovery), but who are not candidates for intensive consolidation therapy (including stem cell transplantation [SCT]).[87]

Maintenance therapy with oral azacitidine should not replace consolidation therapy.

Patients with FLT3-mutated AML who achieve complete remission with midostaurin or quizartinib (in combination with standard induction and consolidation chemotherapy) may continue these agents as monotherapy for maintenance therapy post-consolidation chemotherapy.[84][85][86] Use of midostaurin for maintenance therapy is off-label.

Several oral kinase inhibitors can be considered for post-allogeneic SCT maintenance therapy in patients with FLT3-mutated AML. These include: sorafenib (for FLT3-ITD-mutated only); gilteritinib (for FLT3-ITD-mutated or FLT3-TKD-mutated, particularly if patients are measurable [minimal] residual disease [MRD]-positive before or after SCT); midostaurin (for FLT3-ITD-mutated or FLT3-TKD-mutated); and quizartinib (for FLT3-ITD-mutated only).[38][85][86][88][89][90]

The role of maintenance therapy in the posttransplant setting is still evolving.

See local specialist protocol for dosing guidelines.

Primary options

azacitidine

midostaurin

quizartinib

sorafenib

gilteritinib

complete remission: acute promyelocytic leukemia (APL)

1st line – consolidation therapy

Back

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]).[38][61]

Measurable (minimal) residual disease (MRD) assessment (to detect the PML::RARA fusion transcript) should be carried out following consolidation therapy to evaluate treatment response and guide subsequent treatment.[60][61] 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.[38][60][61] Long-term MRD monitoring is not required for non-high-risk patients in molecular remission following consolidation therapy.

See local specialist protocol for dosing guidelines.

Back

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.

Consider – maintenance therapy

Back

Plus –

intrathecal cytarabine or methotrexate

Treatment recommended for ALL patients in selected patient group

CNS imaging and lumbar puncture should be carried out in patients with neurologic signs and symptoms suggesting CNS involvement.[38]

If CNS disease is confirmed, intrathecal cytarabine or methotrexate should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4 to 6 weeks.[38]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

methotrexate

with high-risk APL

Back

Consider –

maintenance therapy

Treatment recommended for SOME patients in selected patient group

Maintenance therapy may be considered for patients with high-risk APL, but it is not required for non-high-risk patients.[60][61]

Maintenance regimens for APL usually consist of ATRA plus mercaptopurine and methotrexate for 1 to 2 years.[121][122][123]

With close measurable (minimal) residual disease (MRD) monitoring post-consolidation, the role of maintenance therapy is now being challenged.[124][125] 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, reinduction therapy, or clinical trial

Back

1st line –

salvage therapy, reinduction therapy, or clinical trial

Patients with relapsed or refractory AML have a poor prognosis.[108]

There is no standard salvage regimen for relapsed or refractory AML. Where possible, patients should be offered enrollment 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.[23]

Relapse after first complete remission occurs in approximately 50% of patients who have received standard induction therapy, usually in the first year following treatment. 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.[109]

Patients unsuitable for intensive salvage chemotherapy can be considered for low-intensity salvage therapy, which should be continued until disease progression or intolerance. Options include: venetoclax combined with a hypomethylating agent (azacitidine or decitabine) or low-dose subcutaneous cytarabine (LDAraC); gilteritinib (an oral kinase inhibitor) for patients with FLT3-mutated AML; ivosidenib (an IDH1 inhibitor) for patients with IDH1-mutated AML; olutasidenib (an IDH1 inhibitor) for patients with IDH1-mutated AML; enasidenib (an IDH2 inhibitor) for patients with IDH2-mutated AML; and gemtuzumab ozogamicin (single agent) for patients with CD33-positive AML.[102][110][111][112][113][114][115][116]

Important predictors of response to salvage therapy are age, genetic abnormalities, duration of first remission, and history of previous stem cell transplantation (SCT).[117][118][119]

Patients who are unable to tolerate salvage therapy or who decline further treatment should be offered best supportive care and/or palliative care.

Reinduction therapy (with chemotherapy) may be considered for all patients with relapse following long remission (i.e., ≥12 months following induction therapy).[38][60]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

-- AND --

daunorubicin

idarubicin

mitoxantrone

venetoclax

-- AND --

azacitidine

decitabine

cytarabine

gilteritinib

ivosidenib

olutasidenib

enasidenib

gemtuzumab ozogamicin

Consider – stem cell transplantation

Back

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 AML who are unsuitable for or decline standard- or low-intensive chemotherapy should be offered best supportive care.[38][126]

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

Differentiation syndrome: treatments for AML (e.g., ivosidenib, enasidenib, olutasidenib, gilteritinib) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[105][115][127][128] Differentiation syndrome is characterized by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC count (>10,000/microliter [>10 × 10⁹/L]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[61] In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[61]

Hyperleukocytosis: generally defined as a WBC count >100,000/microliter (>100 × 10⁹/L) and is considered a poor prognostic factor. In AML patients, hydroxyurea is recommended for leukoreduction.[23][38] It is recommended that WBC count is lowered to <25,000/microliter (<25 × 10⁹/L), particularly before initiating treatment with hypomethylating agents and venetoclax.[23][38] Urgent leukapheresis may be considered in patients with AML (not including APL) who are symptomatic and have a very high WBC count.[38][61]

Back

Consider –

stem cell transplantation

Treatment recommended for SOME patients in selected patient group

Patients who achieve second remission with intensive salvage chemotherapy should undergo allogeneic stem cell transplantation to reduce the risk of relapse, if they are eligible and a suitable donor is available.[38][60][108]

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

Back

Plus –

intrathecal cytarabine or methotrexate

Treatment recommended for ALL patients in selected patient group

CNS imaging and lumbar puncture should be carried out in patients with neurologic signs and symptoms suggesting CNS involvement.[38]

If CNS disease is confirmed, intrathecal cytarabine or methotrexate should be given two times per week until the cerebrospinal fluid is clear and weekly thereafter for a further 4 to 6 weeks.[38]

See local specialist protocol for dosing guidelines.

Primary options

cytarabine

methotrexate

relapsed or refractory acute promyelocytic leukemia (APL)

Back

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 should be based on previous treatment and whether relapse occurs early or late (definitions vary, but most relapses occur <2 years).[38][60][61] 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.[38][61] 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).[38][61] 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) center and, depending on the MRD status following salvage therapy, an autologous SCT (if MRD negative) or allogeneic SCT (if MRD positive or refractory disease) should be arranged.[38][61]

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

tretinoin

and

daunorubicin

and

cytarabine

gemtuzumab ozogamicin

tretinoin

and

arsenic trioxide

tretinoin

-- AND --

arsenic trioxide

-- AND --

idarubicin

daunorubicin

tretinoin

and

arsenic trioxide

and

gemtuzumab ozogamicin

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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.

Differentiation syndrome: treatments for APL (e.g., ATRA, arsenic trioxide) can cause differentiation syndrome, which can be life-threatening if not treated promptly.[105][115][127][128] Differentiation syndrome is characterized by fever, fluid retention, respiratory distress, pulmonary infiltrates, pulmonary or pericardial effusion, and an elevated WBC count (>10,000/microliter [>10 × 10⁹/L]). Patients should be monitored for hypoxia, pulmonary infiltrates, and pleural effusion. Patients with differentiation syndrome should be promptly treated with dexamethasone.[61] In severe cases, the treatment causing differentiation syndrome may be temporarily discontinued until symptoms resolve.[61]