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

adolescents and adults: newly diagnosed Ph+ B-ALL

1st line – induction therapy (tyrosine kinase inhibitor [TKI] therapy + multiagent therapy or corticosteroid)

Back
ACUTE
|
adolescents and adults: newly diagnosed Ph+ B-ALL
1st line – 

induction therapy (tyrosine kinase inhibitor [TKI] therapy + multiagent therapy or corticosteroid)

Induction therapy is the first phase of treatment. The objective is to achieve complete remission (CR; i.e., eradication of leukemia determined by morphologic criteria).

Treatment regimens and protocols are complex and should be individualized based on ALL subtype, presence of cytogenetic/molecular abnormalities (e.g., Philadelphia chromosome), and patient factors (e.g., age, comorbidities).

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).

Care should be taken to ensure young adults are managed in age-appropriate facilities.

A TKI (e.g., imatinib, dasatinib, bosutinib, nilotinib, ponatinib) combined with multiagent therapy (comprising a corticosteroid and chemotherapy agents) or a corticosteroid should be used for induction therapy in patients with Philadelphia chromosome positive (Ph+) B-ALL.

Asparaginase is commonly added to induction therapy, particularly in adolescents and young adults (ages <40 years).[94]​ There are different formulations of asparaginase. Pegylated (PEG) formulations of Escherichia coli-derived asparaginase (pegaspargase and calaspargase pegol) are usually preferred due to their long half-life and tolerability.[94][95][96][97]​​ Asparaginase Erwinia chrysanthemi (recombinant) is an option for patients who develop hypersensitivity to E coli-derived asparaginase.[98]

Induction therapy regimens for Ph+ B-ALL include (ordered from high to low intensity): TKI plus cyclophosphamide, vincristine, daunorubicin, dexamethasone, cytarabine, methotrexate, PEG-asparaginase, and prednisone (Berlin-Frankfurt-Münster regimen); TKI plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with cytarabine and methotrexate (hyper-CVAD regimen); TKI plus dexamethasone, vincristine, daunorubicin, methotrexate, etoposide, and cytarabine (CALGB 10701 regimen); TKI plus vincristine and dexamethasone; TKI plus a corticosteroid (e.g., prednisone, methylprednisolone, dexamethasone).[57]

High- or moderate-intensity regimens are preferred for adolescents and adults ages <65 years. Older adults (ages ≥65 years) or those with significant comorbidities can be considered for low-intensity regimens.

TKIs target the BCR::ABL fusion protein associated with the Philadelphia chromosome, and they should be given continuously at every phase of treatment (induction, consolidation, maintenance) until relapse or intolerance. If one TKI fails or is intolerable, another TKI should be tried.

Ponatinib is the only TKI that is effective in those harboring the T315I mutation in the ABL kinase domain. In patients with newly diagnosed Ph+ ALL, ponatinib plus multiagent therapy appears to be associated with improved outcomes (e.g., complete molecular response, measurable residual disease [MRD], overall survival) compared with earlier generation TKIs plus multiagent therapy.[113][114] Due to the risk of serious adverse events (e.g., severe cardiovascular events, hepatotoxicity, and posterior reversible encephalopathy syndrome), ponatinib should be used cautiously in patients with associated comorbidities. Ponatinib should be interrupted immediately if serious adverse events occur, and a decision to restart should be guided by a benefit-risk assessment.

A cautious cell reduction phase may be considered before induction therapy for patients with a high leukemic burden (i.e., white blood cell count >100,000/microliter).[116][117]​ This may be achieved with cytarabine, hydroxyurea, and/or corticosteroids. Patients with a high leukemic burden should be closely monitored for tumor lysis syndrome.[53][90]​ See Tumor lysis syndrome. 

Patients who do not achieve a CR following induction therapy are considered to have refractory disease, which has a very poor prognosis.[1][53][90]

MRD assessment should be carried out after induction therapy (along with assessment of CR). Patients with MRD-positive remission may be considered for augmented induction therapy and referral for postinduction therapy with allogeneic stem cell transplantation (SCT).[118]​ Patients with MRD-negative remission can proceed to consolidation therapy as per the chosen treatment protocol.

Patients should at all times be encouraged to participate in a clinical trial, if eligible.

See local specialist protocol for dosing guidelines.

Primary options

TKI + Berlin-Frankfurt-Münster regimen

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

cyclophosphamide

and

vincristine

and

daunorubicin

and

dexamethasone

and

cytarabine

and

methotrexate

and

prednisone

-- AND --

pegaspargase

or

calaspargase pegol

or

asparaginase erwinia chrysanthemi (recombinant)

OR

TKI + hyper-CVAD regimen

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

cyclophosphamide

and

vincristine

and

doxorubicin

and

dexamethasone

and

cytarabine

and

methotrexate

OR

TKI + CALGB 10701 regimen

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

dexamethasone

and

vincristine

and

daunorubicin

and

methotrexate

and

etoposide

and

cytarabine

OR

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

vincristine

and

dexamethasone

OR

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

prednisone

or

methylprednisolone

or

dexamethasone

Plus – CNS prophylaxis or treatment

Back
ACUTE
|
adolescents and adults: newly diagnosed Ph+ B-ALL
Plus – 

CNS prophylaxis or treatment

Treatment recommended for ALL patients in selected patient group

All patients should receive CNS-directed prophylaxis or CNS-directed treatment (if CNS disease is detected) at every stage of treatment.

Patients can develop a CNS relapse despite receiving CNS prophylaxis, though this generally develops after completion of the treatment course.[67]

CNS involvement can lead to severe neurologic morbidity (e.g., cranial nerve palsies), and is a major obstacle to cure, accounting for up to 40% of initial relapses in clinical trials.[82][83][84] Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic stem cell transplanation (SCT).[59][69]

CNS-directed prophylaxis consists of induction therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[52][57][126]​ Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[57] The specific timing, frequency, and agents used will vary depending on the treatment protocol.

Intraventricular therapy via an Ommaya reservoir should be considered if the intrathecal route is not possible.

If CNS disease is present, the recommended treatment regimen is often similar to the prophylactic regimen except the frequency of intrathecal injections may be increased (e.g., twice-weekly).

Potential adverse effects of CNS prophylaxis or treatment include acute or chronic neurotoxicity presenting as pyrexia, arachnoiditis, leukoencephalopathy, and milder subclinical CNS dysfunctions.[52][126]

Cranial or craniospinal irradiation is effective at preventing and treating CNS disease but can lead to severe adverse effects, such as neurocognitive dysfunction and secondary malignancies. Currently, it is usually reserved for treatment of overt CNS disease at diagnosis or relapse, or as prophylaxis in certain high-risk patients, or as part of a clinical trial.​[69][127]

See local specialist protocol for dosing guidelines.

Primary options

Intrathecal therapy

methotrexate

OR

Triple intrathecal therapy

methotrexate

and

cytarabine

and

hydrocortisone sodium succinate

Plus – supportive care

Back
ACUTE
|
adolescents and adults: newly diagnosed Ph+ B-ALL
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 the following complications.

Tumor lysis syndrome (TLS): an oncologic emergency. Use vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricemic agents (e.g., allopurinol or rasburicase) to prevent or treat TLS. TLS is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and/or elevated serum lactate dehydrogenase, which can occur following chemotherapy (or spontaneously in rare cases), particularly if WBC count (tumor burden) is high. TLS can lead to cardiac arrhythmias, seizures, acute renal failure, and death, if untreated. See Tumor lysis syndrome.

Infections and febrile neutropenia: use antibiotics, antifungals, and antivirals to prevent or treat infections and febrile neutropenia.[56][155][156][157][158] [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ]  Risk of infection is greatest following induction chemotherapy when neutropenia is profound and prolonged. Febrile neutropenia is an oncologic emergency. Mortality rate associated with febrile neutropenia in hospitalized patients with leukemia is reported to be approximately 14%.[159]​ Use of granulocyte colony-stimulating factors (G-CSFs; e.g., filgrastim, pegfilgrastim) to prevent febrile neutropenia is recommended during myelosuppressive therapy or as directed by the treatment protocol.[57][160]​ See Febrile neutropenia. 

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[161][162] [ Cochrane Clinical Answers logo ] ​ Risk of bleeding complications is highest during induction therapy due to bone marrow suppression. Blood products should be irradiated, leukocyte-depleted, and cytomegalovirus-negative.[57]

Severe thrombocytopenia: use norethindrone (or a similar drug) in female patients of menstruating age to suppress menses.

Cardiotoxicity: use of dexrazoxane with chemotherapy to prevent cardiotoxicity (e.g., when cumulative dose of doxorubicin is ≥300 mg/m²), though experience with this agent in adults is limited.[163]

Oral mucositis: mouth care should be initiated to minimize oral mucositis.

Symptomatic leukostasis (hyperleukocytosis): leukapheresis may be considered in patients with symptomatic leukostasis prior to initiation of induction therapy. Systemic therapy (e.g., cytarabine, hydroxyurea, and/or corticosteroids) can also achieve urgent cytoreduction in this situation.

Fertility counseling and fertility preservation should be discussed with all patients. Fertility preservation for male patients includes semen cryopreservation postpuberty. Options for female patients are limited and merit discussion with the fertility center. There will typically be insufficient time to stimulate oocyte production to allow oocyte or embryo (if a partner is available) cryopreservation. Furthermore, cryopreserved ovarian tissue from female patients with ALL can harbor malignant cells, which may cause disease recurrence when reimplanted.[164]

adolescents and adults: newly diagnosed Ph-negative B-ALL or T-ALL

1st line – induction therapy (multiagent therapy)

Back
ACUTE
|
adolescents and adults: newly diagnosed Ph-negative B-ALL or T-ALL
1st line – 

induction therapy (multiagent therapy)

Induction therapy is the first phase of treatment. The objective is to achieve complete remission (CR; i.e., eradication of leukemia determined by morphologic criteria).

Treatment regimens and protocols are complex and should be individualized based on ALL subtype, presence of cytogenetic/molecular abnormalities (e.g., Philadelphia chromosome), and patient factors (e.g., age, comorbidities).

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).

Care should be taken to ensure young adults are managed in age-appropriate facilities.

Multiagent therapy (comprising a corticosteroid and chemotherapy agents) should be used for induction therapy in patients with Philadelphia chromosome negative (Ph-negative) B-ALL and those with T-ALL.

Asparaginase is commonly added to induction therapy, particularly in adolescents and young adults (ages <40 years).[94] There are different formulations of asparaginase. Pegylated (PEG) formulations of Escherichia coli-derived asparaginase (pegaspargase and calaspargase pegol) are usually preferred due to their long half-life and tolerability.[94][95][96][97]​ Asparaginase Erwinia chrysanthemi (recombinant) is an option for patients who develop hypersensitivity to E coli-derived asparaginase.[98]

Induction therapy regimens for Ph-negative B-ALL and T-ALL include: daunorubicin, vincristine, prednisone, and PEG-asparaginase (CALGB 10403, COG AALL0434, and Linker 4-drug regimens); doxorubicin, vincristine, prednisone, methotrexate, and PEG-asparaginase (DFCI ALL regimen); daunorubicin, vincristine, prednisone, PEG-asparaginase, and cyclophosphamide (GRAALL-2005, CALGB 8811, and PETHEMA ALL-96 regimens); hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with cytarabine and methotrexate (hyper-CVAD regimen); daunorubicin, vincristine, prednisone, methotrexate, and PEG-asparaginase (USC/MSKCC ALL regimen); daunorubicin, vincristine, prednisone, and PEG-asparaginase (induction phase 1), followed by cyclophosphamide, cytarabine, and mercaptopurine (induction phase 2) (ECOG1910 regimen [for Ph-negative B-ALL]).[57]

Intense pediatric-inspired protocols are preferred for adolescents and young adults (i.e., ages <40 years).[57][92][115]​ Pediatric-inspired protocols generally have larger cumulative doses of non-myelosuppressive drugs such as corticosteroids, vincristine, and asparaginase; longer and more intense CNS-directed therapy; and a lower tendency for allogeneic stem cell transplantation (SCT) in first remission. Older adults (ages ≥65 years) or those with significant comorbidities may receive multiagent therapy with dose modifications, or palliative corticosteroids. 

A cautious cell reduction phase may be considered before induction therapy for patients with a high leukemic burden (i.e., white blood cell count >100,000/microliter).[116][117] This may be achieved with cytarabine, hydroxyurea, and/or corticosteroids Patients with a high leukemic burden should be closely monitored for tumor lysis syndrome.[53][90] See Tumor lysis syndrome. 

Patients who do not achieve a CR following induction therapy are considered to have refractory disease, which has a very poor prognosis.[1][53][90]

Measurable residual disease (MRD) assessment should be carried out after induction therapy (along with assessment of CR). Patients with MRD-positive remission may be considered for augmented induction therapy and referral for postinduction therapy with allogeneic SCT.[118]​ Patients with MRD-negative remission can proceed to consolidation therapy as per the chosen treatment protocol.

Patients should at all times be encouraged to participate in a clinical trial, if eligible.

See local specialist protocol for dosing guidelines.

Primary options

CALGB 10403, COG AALL0434, and Linker 4-drug regimens

daunorubicin

and

vincristine

and

prednisone

-- AND --

pegaspargase

or

calaspargase pegol

or

asparaginase erwinia chrysanthemi (recombinant)

OR

DFCI ALL regimen

doxorubicin

and

vincristine

and

prednisone

and

methotrexate

-- AND --

pegaspargase

or

calaspargase pegol

or

asparaginase erwinia chrysanthemi (recombinant)

OR

GRAALL-2005, CALGB 8811, and PETHEMA ALL-96 regimens

daunorubicin

and

vincristine

and

prednisone

and

cyclophosphamide

-- AND --

pegaspargase

or

calaspargase pegol

or

asparaginase erwinia chrysanthemi (recombinant)

OR

Hyper-CVAD regimen

cyclophosphamide

and

vincristine

and

doxorubicin

and

dexamethasone

and

cytarabine

and

methotrexate

OR

USC/MSKCC ALL regimen

daunorubicin

and

vincristine

and

prednisone

and

methotrexate

-- AND --

pegaspargase

or

calaspargase pegol

or

asparaginase erwinia chrysanthemi (recombinant)

OR

ECOG1910 regimen (for Ph-negative B-ALL)

daunorubicin

and

vincristine

and

prednisone

and

cyclophosphamide

and

cytarabine

and

mercaptopurine

-- AND --

pegaspargase

or

calaspargase pegol

or

asparaginase erwinia chrysanthemi (recombinant)

Plus – CNS prophylaxis or treatment

Back
ACUTE
|
adolescents and adults: newly diagnosed Ph-negative B-ALL or T-ALL
Plus – 

CNS prophylaxis or treatment

Treatment recommended for ALL patients in selected patient group

All patients should receive CNS-directed prophylaxis or CNS-directed treatment (if CNS disease is detected) at every stage of treatment.

Patients can develop a CNS relapse despite receiving CNS prophylaxis, though this generally develops after completion of the treatment course.[67]

CNS involvement can lead to severe neurologic morbidity (e.g., cranial nerve palsies), and is a major obstacle to cure, accounting for up to 40% of initial relapses in clinical trials.[82][83][84] Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic stem cell transplantation (SCT).[59][69]

CNS-directed prophylaxis consists of induction therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[52][57][126] Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[57] The specific timing, frequency, and agents used will vary depending on the treatment protocol.

Intraventricular therapy via an Ommaya reservoir should be considered if the intrathecal route is not possible.

If CNS disease is present, the recommended treatment regimen is often similar to the prophylactic regimen except the frequency of intrathecal injections may be increased (e.g., twice-weekly).

Potential adverse effects of CNS prophylaxis or treatment include acute or chronic neurotoxicity presenting as pyrexia, arachnoiditis, leukoencephalopathy, and milder subclinical CNS dysfunctions.[52][126]

Cranial or craniospinal irradiation is effective at preventing and treating CNS disease but can lead to severe adverse effects, such as neurocognitive dysfunction and secondary malignancies. Currently, it is usually reserved for treatment of overt CNS disease at diagnosis or relapse, or as prophylaxis in certain high-risk patients, or as part of a clinical trial.[69][127]​ 

See local specialist protocol for dosing guidelines.

Primary options

Intrathecal therapy

methotrexate

OR

Triple intrathecal therapy

methotrexate

and

cytarabine

and

hydrocortisone sodium succinate

Plus – supportive care

Back
ACUTE
|
adolescents and adults: newly diagnosed Ph-negative B-ALL or T-ALL
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 the following complications.

Tumor lysis syndrome (TLS): an oncologic emergency. Use vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricemic agents (e.g., allopurinol or rasburicase) to prevent or treat TLS. TLS is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and/or elevated serum lactate dehydrogenase, which can occur following chemotherapy (or spontaneously in rare cases), particularly if WBC count (tumor burden) is high. TLS can lead to cardiac arrhythmias, seizures, acute renal failure, and death, if untreated. See Tumor lysis syndrome.

Infections and febrile neutropenia: use antibiotics, antifungals, and antivirals to prevent or treat infections and febrile neutropenia.[56][155][156][157][158] [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] Risk of infection is greatest following induction chemotherapy when neutropenia is profound and prolonged. Febrile neutropenia is an oncologic emergency. Mortality rate associated with febrile neutropenia in hospitalized patients with leukemia is reported to be approximately 14%.[159]​ Use of granulocyte colony-stimulating factors (G-CSFs; e.g., filgrastim, pegfilgrastim) to prevent febrile neutropenia is recommended during myelosuppressive therapy or as directed by the treatment protocol.[57][160] See Febrile neutropenia. 

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[161][162] [ Cochrane Clinical Answers logo ] ​ Risk of bleeding complications is highest during induction therapy due to bone marrow suppression. Blood products should be irradiated, leukocyte-depleted, and cytomegalovirus-negative.[57]

Severe thrombocytopenia: use norethindrone (or a similar drug) in female patients of menstruating age to suppress menses.

Cardiotoxicity: use of dexrazoxane with chemotherapy to prevent cardiotoxicity (e.g., when cumulative dose of doxorubicin is ≥300 mg/m²), though experience with this agent in adults is limited.[163]

Oral mucositis: mouth care should be initiated to minimize oral mucositis.

Symptomatic leukostasis (hyperleukocytosis): leukapheresis may be considered in patients with symptomatic leukostasis prior to initiation of induction therapy. Systemic therapy (e.g., cytarabine, hydroxyurea, and/or corticosteroids) can also achieve urgent cytoreduction in this situation.

Fertility counseling and fertility preservation should be discussed with all patients. Fertility preservation for male patients includes semen cryopreservation postpuberty. Options for female patients are limited and merit discussion with the fertility center. There will typically be insufficient time to stimulate oocyte production to allow oocyte or embryo (if a partner is available) cryopreservation. Furthermore, cryopreserved ovarian tissue from female patients with ALL can harbor malignant cells, which may cause disease recurrence when reimplanted.[164]

Plus – rituximab

Back
ACUTE
|
adolescents and adults: newly diagnosed Ph-negative B-ALL or T-ALL
|
with CD20+ Ph-negative B-ALL
Plus – 

rituximab

Treatment recommended for ALL patients in selected patient group

Patients with CD20+ Ph-negative B-ALL can be treated with rituximab (an anti-CD20 monoclonal antibody) in addition to induction therapy.

In one randomized study, rituximab improved event-free survival in patients with CD20+ Ph-negative B-ALL, especially young adults.[112]​ In this study, rituximab was given during all treatment phases (including maintenance). 

See local specialist protocol for dosing guidelines.

Primary options

rituximab

ONGOING

complete remission: standard-risk Ph-negative B-ALL or T-ALL

1st line – consolidation therapy

Back
ONGOING
|
complete remission: standard-risk Ph-negative B-ALL or T-ALL
1st line – 

consolidation therapy

Consolidation therapy is the second phase of treatment (following induction therapy).

The goal of consolidation therapy is to eliminate clinically undetectable residual leukemia, hence preventing relapse and the development of drug-resistant cells. This phase is known to prolong leukemia-free survival.

Risk stratification is used to guide consolidation therapy and potential allogeneic stem cell transplantation (SCT) to improve relapse-free survival.

Patients can be identified as standard risk based on the following:

white blood cell count at presentation (e.g., ≤30,000/microliter for B-ALL and ≤100,000/microliter for T-ALL for adults);

favorable cytogenetic and molecular profile (e.g., ETV6::RUNX1 [also known as TEL::AML1]) [see Diagnostic criteria];

favorable immunophenotypic subtype (e.g., CD20-negative);

response to induction therapy (i.e., achieving complete remission [CR]);

absent or low measurable residual disease (MRD; e.g., <0.01%) following induction therapy.[57][77][81]

Consolidation is achieved with the use of dose-intense multiagent therapy. Consolidation regimens will vary depending on the treatment protocol, but they commonly incorporate methotrexate, cytarabine, mercaptopurine, cyclophosphamide, vincristine, corticosteroids (e.g., dexamethasone), and asparaginase.[57][119]​ Drugs used for induction therapy can also be used for consolidation therapy.[57]

See local specialist protocol for regimens and dosing guidelines.

Consider – maintenance therapy

Back
ONGOING
|
complete remission: standard-risk Ph-negative B-ALL or T-ALL
Consider – 

maintenance therapy

Treatment recommended for SOME patients in selected patient group

Maintenance therapy is the third phase of treatment (following induction and consolidation therapy).

The goal of maintenance therapy is to eliminate measurable residual disease (MRD) and maintain long-term remission.

Maintenance therapy is recommended for all patients in first complete remission (CR1) who do not undergo allogeneic stem cell transplantation (SCT).[57]

Standard maintenance regimen usually includes monthly vincristine and prednisone combined with daily mercaptopurine and weekly methotrexate (for 2-3 years). However, the optimal maintenance drug regimen is unknown. Some international cooperative groups are reducing the duration of maintenance therapy for boys.[124]

Thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) phenotype may be assessed at diagnosis to allow individualized dosing of mercaptopurine.[70]

Maintenance therapy is not recommended for patients with mature B-ALL (Burkitt lymphoma/leukemia). Patients with mature B-ALL usually achieve long-term remission following early intensive therapy, and most relapses occur early (within 1 year).[57][123]

See local specialist protocol for dosing guidelines.

Primary options

vincristine

and

prednisone

and

mercaptopurine

and

methotrexate

Plus – CNS prophylaxis or treatment

Back
ONGOING
|
complete remission: standard-risk Ph-negative B-ALL or T-ALL
Plus – 

CNS prophylaxis or treatment

Treatment recommended for ALL patients in selected patient group

All patients should receive CNS-directed prophylaxis or CNS-directed treatment (if CNS disease is detected) at every stage of treatment.

Patients can develop a CNS relapse despite receiving CNS prophylaxis, though this generally develops after completion of the treatment course.[67]

CNS involvement can lead to severe neurologic morbidity (e.g., cranial nerve palsies), and is a major obstacle to cure, accounting for up to 40% of initial relapses in clinical trials.[82][83][84]​​ Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic stem cell transplantation (SCT).[59][69]

CNS-directed prophylaxis consists of consolidation therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[52][57][126]​ Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[57] The specific timing, frequency, and agents used will vary depending on the treatment protocol.

Intraventricular therapy via an Ommaya reservoir should be considered if the intrathecal route is not possible.

If CNS disease is present, the recommended treatment regimen is often similar to the prophylactic regimen except the frequency of intrathecal injections may be increased (e.g., twice-weekly).

Potential adverse effects of CNS prophylaxis or treatment include acute or chronic neurotoxicity presenting as pyrexia, arachnoiditis, leukoencephalopathy, and milder subclinical CNS dysfunctions.[52][126] 

Cranial or craniospinal irradiation is effective at preventing and treating CNS disease but can lead to severe adverse effects, such as neurocognitive dysfunction and secondary malignancies. Currently, it is usually reserved for treatment of overt CNS disease at diagnosis or relapse, or as prophylaxis in certain high-risk patients, or as part of a clinical trial.​[69][127]

See local specialist protocol for dosing guidelines.

Primary options

Intrathecal therapy

methotrexate

OR

Triple intrathecal therapy

methotrexate

and

cytarabine

and

hydrocortisone sodium succinate

Plus – supportive care

Back
ONGOING
|
complete remission: standard-risk Ph-negative B-ALL or T-ALL
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 the following complications.

Tumor lysis syndrome (TLS): an oncologic emergency. Use vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricemic agents (e.g., allopurinol or rasburicase) to prevent or treat TLS. TLS is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and/or elevated serum lactate dehydrogenase, which can occur following chemotherapy (or spontaneously in rare cases), particularly if WBC count (tumor burden) is high. TLS can lead to cardiac arrhythmias, seizures, acute renal failure, and death, if untreated. See Tumor lysis syndrome.

Infections and febrile neutropenia: use antibiotics, antifungals, and antivirals to prevent or treat infections and febrile neutropenia.[56][155][156][157][158] [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] ​​ Risk of infection is greatest following induction chemotherapy when neutropenia is profound and prolonged. Febrile neutropenia is an oncologic emergency. Mortality rate associated with febrile neutropenia in hospitalized patients with leukemia is reported to be approximately 14%.[159]​ Use of granulocyte colony-stimulating factors (G-CSFs; e.g., filgrastim, pegfilgrastim) to prevent febrile neutropenia is recommended during myelosuppressive therapy or as directed by the treatment protocol.[57][160]​ See Febrile neutropenia.

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[161][162] [ Cochrane Clinical Answers logo ]  Risk of bleeding complications is highest during induction therapy due to bone marrow suppression. Blood products should be irradiated, leukocyte-depleted, and cytomegalovirus-negative.[57]

Severe thrombocytopenia: use norethindrone (or a similar drug) in female patients of menstruating age to suppress menses.

Cardiotoxicity: use of dexrazoxane with chemotherapy to prevent cardiotoxicity (e.g., when cumulative dose of doxorubicin is ≥300 mg/m²), though experience with this agent in adults is limited.[163]

Oral mucositis: mouth care should be initiated to minimize oral mucositis.

Symptomatic leukostasis (hyperleukocytosis): leukapheresis may be considered in patients with symptomatic leukostasis prior to initiation of induction therapy. Systemic therapy (e.g., cytarabine, hydroxyurea, and/or corticosteroids) can also achieve urgent cytoreduction in this situation.

Fertility counseling and fertility preservation should be discussed with all patients. Fertility preservation for male patients includes semen cryopreservation postpuberty. Options for female patients are limited and merit discussion with the fertility center. There will typically be insufficient time to stimulate oocyte production to allow oocyte or embryo (if a partner is available) cryopreservation. Furthermore, cryopreserved ovarian tissue from female patients with ALL can harbor malignant cells, which may cause disease recurrence when reimplanted.[164]

complete remission: Ph+ B-ALL and high-risk Ph-negative B-ALL or T-ALL

1st line – consolidation therapy

Back
ONGOING
|
complete remission: Ph+ B-ALL and high-risk Ph-negative B-ALL or T-ALL
1st line – 

consolidation therapy

Consolidation therapy is the second phase of treatment (following induction therapy).

The goal of consolidation therapy is to eliminate clinically undetectable residual leukemia, hence preventing relapse and the development of drug-resistant cells. This phase is known to prolong leukemia-free survival.

Risk stratification is used to guide consolidation therapy and potential allogeneic stem cell transplantation (SCT) to improve relapse-free survival.

Patients can be identified as high risk based on the following:

age (adults >35 years of age are considered high risk);

white blood cell count at presentation (e.g., >30,000/microliter for B-ALL and >100,000/microliter for T-ALL are considered high risk for adults);

unfavorable cytogenetic or molecular profile (e.g., KMT2A rearranged; see Diagnostic criteria); 

unfavorable immunophenotypic subtype (e.g., CD20+);

poor response to induction therapy (i.e., not achieving complete remission [CR]);

presence of measurable residual disease (MRD; e.g., ≥0.01%) following induction therapy.[57][77][81]

Consolidation is achieved with the use of dose-intense multiagent therapy. Consolidation regimens will vary depending on the treatment protocol, but they commonly incorporate methotrexate, cytarabine, mercaptopurine, cyclophosphamide, vincristine, corticosteroids (e.g., dexamethasone), and asparaginase.[57][119]​ Drugs used for induction therapy can also be used for consolidation therapy.[57]

Patients with B-ALL in first or second complete remission (CR1 or CR2) following induction therapy who have MRD ≥0.1% can be treated with blinatumomab (a bispecific CD19-directed CD3 T-cell engager) as an alternative to consolidation chemotherapy (i.e., as a bridge to allogeneic SCT). In an open-label trial, 88 (78%) of 113 patients with B-ALL in complete hematologic remission with MRD ≥0.1% achieved a complete MRD response with blinatumomab.[122] MRD responders had significantly longer relapse-free survival and overall survival compared with MRD nonresponders.[122] Adverse events included severe and life-threatening cytokine release syndrome and neurologic toxicity.[122]

See local specialist protocol for regimens and dosing guidelines.

Consider – maintenance therapy

Back
ONGOING
|
complete remission: Ph+ B-ALL and high-risk Ph-negative B-ALL or T-ALL
Consider – 

maintenance therapy

Treatment recommended for SOME patients in selected patient group

Maintenance therapy is the third phase of treatment (following induction and consolidation therapy). The goal of maintenance therapy is to eliminate measurable residual disease (MRD) and maintain long-term remission.

Maintenance therapy is recommended for all patients in first complete remission (CR1) who do not undergo allogeneic stem cell transplantation (SCT).[57]

Standard maintenance regimen usually includes monthly vincristine and prednisone combined with daily mercaptopurine and weekly methotrexate (for 2-3 years). However, the optimal maintenance drug regimen is unknown. Some international cooperative groups are reducing the duration of maintenance therapy for boys.[124]

Thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) phenotype may be assessed at diagnosis to allow individualized dosing of mercaptopurine.[70]

Maintenance therapy is not recommended for patients with mature B-ALL (Burkitt lymphoma/leukemia). Patients with mature B-ALL usually achieve long-term remission following early intensive therapy, and most relapses occur early (within 1 year).[57][123]

See local specialist protocol for dosing guidelines.

Primary options

vincristine

and

prednisone

and

mercaptopurine

and

methotrexate

Consider – stem cell transplantation (SCT)

Back
ONGOING
|
complete remission: Ph+ B-ALL and high-risk Ph-negative B-ALL or T-ALL
Consider – 

stem cell transplantation (SCT)

Treatment recommended for SOME patients in selected patient group

Allogeneic SCT may be used as consolidation therapy in lieu of further systemic therapy in selected patients (e.g., those with high-risk features), if eligible.[118][120][121]

Allogeneic SCT (from a matched sibling donor or matched unrelated donor) is recommended for patients with Ph+ B-ALL in first complete remission (CR1), if eligible (e.g., based on age, comorbidities, performance status).[120][121] Deferring allogeneic SCT (and continuing systemic therapy for consolidation and maintenance) may be an option in some patients with Ph+ B-ALL. In one phase 2 study of young Ph+ ALL patients (age ≤21 years) who achieved MRD negativity after induction therapy, allogeneic SCT offered no advantage over multiagent therapy plus a tyrosine kinase inhibitor (TKI).[105] In a retrospective study of Ph+ B-ALL patients who achieved complete molecular remission within 90 days of starting treatment, allogeneic SCT did not improve survival compared with multiagent therapy plus a TKI.[128]

Allogeneic SCT is recommended for patients with high-risk Ph-negative B-ALL or T-ALL in CR1, if eligible.[118][121] There is some evidence supporting its use in patients with standard-risk disease in CR1, but this is controversial and not standard practice.[121][129]

Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic SCT.[59][69]

The optimal timing for allogeneic SCT is unclear. However, it is recommended that MRD negativity should be achieved before proceeding to allogeneic SCT as this can improve outcomes.[57][130][131]

Once a donor has been found, patients suitable for allogeneic SCT should undergo myeloablative conditioning (typically with total body irradiation and chemotherapy [e.g., cyclophosphamide or etoposide]) to induce bone marrow ablation and to provide sufficient immunosuppression to prevent allograft injury by residual host cells.[121] Reduced-intensity conditioning regimens may be considered for older and less fit patients.[121]

Donor stem cells can be obtained from bone marrow or peripheral blood.[132] Umbilical cord blood is an alternative stem cell source.[133][134]

Complications of SCT include graft-versus-host disease (GVHD), graft rejection pulmonary complications (presenting as fever, pulmonary infiltrates, hypoxia, and adult respiratory distress syndrome), and veno-occlusive disease. One randomized study found that the inclusion of antithymocyte globulin in the conditioning regimen reduced the incidence of GVHD after allogeneic SCT.[135]

Plus – CNS prophylaxis or treatment

Back
ONGOING
|
complete remission: Ph+ B-ALL and high-risk Ph-negative B-ALL or T-ALL
Plus – 

CNS prophylaxis or treatment

Treatment recommended for ALL patients in selected patient group

All patients should receive CNS-directed prophylaxis or CNS-directed treatment (if CNS disease is detected) at every stage of treatment.

Patients can develop a CNS relapse despite receiving CNS prophylaxis, though this generally develops after completion of the treatment course.[67]

CNS involvement can lead to severe neurologic morbidity (e.g., cranial nerve palsies), and is a major obstacle to cure, accounting for up to 40% of initial relapses in clinical trials.[82][83][84]​ Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic stem cell transplantation (SCT).[59][69]

CNS-directed prophylaxis consists of consolidation therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[52][57][126] Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[57] The specific timing, frequency, and agents used will vary depending on the treatment protocol.

Intraventricular therapy via an Ommaya reservoir should be considered if the intrathecal route is not possible.

If CNS disease is present, the recommended treatment regimen is often similar to the prophylactic regimen except the frequency of intrathecal injections may be increased (e.g., twice-weekly).

Potential adverse effects of CNS prophylaxis or treatment include acute or chronic neurotoxicity presenting as pyrexia, arachnoiditis, leukoencephalopathy, and milder subclinical CNS dysfunctions.[52][126]

Cranial or craniospinal irradiation is effective at preventing and treating CNS disease but can lead to severe adverse effects, such as neurocognitive dysfunction and secondary malignancies. Currently, it is usually reserved for treatment of overt CNS disease at diagnosis or relapse, or as prophylaxis in certain high-risk patients, or as part of a clinical trial.[69][127]

See local specialist protocol for dosing guidelines.

Primary options

Intrathecal therapy

methotrexate

OR

Triple intrathecal therapy

methotrexate

and

cytarabine

and

hydrocortisone sodium succinate

Plus – supportive care

Back
ONGOING
|
complete remission: Ph+ B-ALL and high-risk Ph-negative B-ALL or T-ALL
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 the following complications.

Tumor lysis syndrome (TLS): an oncologic emergency. Use vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricemic agents (e.g., allopurinol or rasburicase) to prevent or treat TLS. TLS is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and/or elevated serum lactate dehydrogenase, which can occur following chemotherapy (or spontaneously in rare cases), particularly if WBC count (tumor burden) is high. TLS can lead to cardiac arrhythmias, seizures, acute renal failure, and death, if untreated. See Tumor lysis syndrome.

Infections and febrile neutropenia: use antibiotics, antifungals, and antivirals to prevent or treat infections and febrile neutropenia.[56][155][156][157][158] [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] Risk of infection is greatest following induction chemotherapy when neutropenia is profound and prolonged. Febrile neutropenia is an oncologic emergency. Mortality rate associated with febrile neutropenia in hospitalized patients with leukemia is reported to be approximately 14%.[159] Use of granulocyte colony-stimulating factors (G-CSFs; e.g., filgrastim, pegfilgrastim) to prevent febrile neutropenia is recommended during myelosuppressive therapy or as directed by the treatment protocol.[57][160] See Febrile neutropenia.

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[161][162] [ Cochrane Clinical Answers logo ] Risk of bleeding complications is highest during induction therapy due to bone marrow suppression. Blood products should be irradiated, leukocyte-depleted, and cytomegalovirus-negative.[57]

Severe thrombocytopenia: use norethindrone (or a similar drug) in female patients of menstruating age to suppress menses.

Cardiotoxicity: use of dexrazoxane with chemotherapy to prevent cardiotoxicity (e.g., when cumulative dose of doxorubicin is ≥300 mg/m²), though experience with this agent in adults is limited.[163]

Oral mucositis: mouth care should be initiated to minimize oral mucositis.

Symptomatic leukostasis (hyperleukocytosis): leukapheresis may be considered in patients with symptomatic leukostasis prior to initiation of induction therapy. Systemic therapy (e.g., cytarabine, hydroxyurea, and/or corticosteroids) can also achieve urgent cytoreduction in this situation.

Fertility counseling and fertility preservation should be discussed with all patients. Fertility preservation for male patients includes semen cryopreservation postpuberty. Options for female patients are limited and merit discussion with the fertility center. There will typically be insufficient time to stimulate oocyte production to allow oocyte or embryo (if a partner is available) cryopreservation. Furthermore, cryopreserved ovarian tissue from female patients with ALL can harbor malignant cells, which may cause disease recurrence when reimplanted.[164]

Plus – tyrosine kinase inhibitor (TKI)

Back
ONGOING
|
complete remission: Ph+ B-ALL and high-risk Ph-negative B-ALL or T-ALL
|
with Ph+ B-ALL
Plus – 

tyrosine kinase inhibitor (TKI)

Treatment recommended for ALL patients in selected patient group

Patients with Philadelphia chromosome positive (Ph+) B-ALL are treated with a TKI (e.g., imatinib, dasatinib, bosutinib, nilotinib, ponatinib), which should be given continuously at every phase of treatment (induction, consolidation, maintenance) until relapse or intolerance.

If one TKI fails or is intolerable, another TKI should be tried.

TKIs target the BCR::ABL fusion protein associated with the Philadelphia chromosome.

Ponatinib is the only TKI that is effective in those harboring the T315I mutation in the ABL kinase domain. In patients with newly diagnosed Ph+ ALL, ponatinib plus multiagent therapy appears to be associated with improved outcomes (e.g., complete molecular response, measurable residual disease [MRD], overall survival) compared with earlier generation TKIs plus multiagent therapy.[113][114]

Due to the risk of serious adverse events (e.g., severe cardiovascular events, hepatotoxicity, and posterior reversible encephalopathy syndrome), ponatinib should be used cautiously in patients with associated comorbidities. Ponatinib should be interrupted immediately if serious adverse events occur, and a decision to restart should be guided by a benefit-risk assessment.

For patients undergoing allogeneic SCT, the National Comprehensive Cancer Network (NCCN) recommends that TKI therapy should be resumed as soon as feasible post-transplant and continued for at least 2 years in patients with Ph+ B-ALL.[57]​ A European expert panel recommends continuing TKI therapy until 12 months of continuous MRD negativity is achieved post-transplant (for patients in CR1).[136]​ The benefits of post-transplant TKI therapy in patients with Ph+ B-ALL are unclear due to limited evidence from randomized studies; however, some data suggest improved overall survival, especially in MRD-positive patients.[136][137]​​

The optimal duration of TKI therapy during maintenance is unclear as late molecular relapses can occur following discontinuation of maintenance TKI.[125]

See local specialist protocol for dosing guidelines.

Primary options

imatinib

OR

dasatinib

OR

bosutinib

OR

nilotinib

OR

ponatinib

Consider – rituximab (with consolidation therapy)

Back
ONGOING
|
complete remission: Ph+ B-ALL and high-risk Ph-negative B-ALL or T-ALL
|
with CD20+ Ph-negative B-ALL
Consider – 

rituximab (with consolidation therapy)

Treatment recommended for SOME patients in selected patient group

Patients with CD20+ Ph-negative B-ALL can be treated with rituximab (an anti-CD20 monoclonal antibody) in addition to consolidation therapy. Rituximab is not used for maintenance therapy.

In one randomized study, rituximab improved event-free survival in patients with CD20+ Ph-negative B-ALL, especially young adults.[112]​​ In this study, rituximab was given during all treatment phases (including maintenance).

See local specialist protocol for dosing guidelines.

Primary options

rituximab

relapsed or refractory disease

1st line – salvage chemotherapy or immunotherapy ± stem cell transplantation (SCT) and/or donor lymphocyte infusion

Back
ONGOING
|
relapsed or refractory disease
1st line – 

salvage chemotherapy or immunotherapy ± stem cell transplantation (SCT) and/or donor lymphocyte infusion

Patients who do not achieve complete remission (CR), or who relapse, should be considered for salvage therapy.

There is no universally accepted treatment approach for salvage therapy; therefore, treatment should be individualized based on performance status, comorbidities, transplant options, and duration of first response.

Patients should be encouraged to enter a clinical trial.

Salvage therapy with conventional chemotherapy may be considered for relapsed or refractory disease, but response is often poor.[138][139][140][141] If relapse occurs ≥3 years from diagnosis (i.e., late relapse), the same regimen used for induction therapy can be considered for salvage therapy.[57]

The following antigen-specific immunotherapies are approved for patients with relapsed or refractory B-ALL, but the optimal sequence is unknown:[142]

blinatumomab (a CD19-directed CD3 T-cell engager)

inotuzumab ozogamicin (a CD22-targeted humanized monoclonal antibody conjugated to the cytotoxic agent calicheamicin)

tisagenlecleucel (a CD19-targeted chimeric antigen receptor [CAR] T-cell immunotherapy)

brexucabtagene autoleucel (a CD19-targeted CAR T-cell immunotherapy).

Immunotherapies are associated with serious adverse effects. Severe hepatotoxicity (including veno-occlusive liver disease) may occur with inotuzumab ozogamicin.[146][149][150] Cytokine release syndrome (CRS) and neurologic toxicity may occur with blinatumomab and CD19-targeted CAR T-cell immunotherapies.[147][151][152] Tocilizumab is recommended for the management of patients with prolonged or severe CAR T-cell-associated CRS.[153]​ T-cell malignancies may also occur following treatment with CD19-targeted CAR T-cell immunotherapies.[154]​ Some cases have occured weeks after treatment, and some have been fatal.

Patients with relapsed disease who achieve a second CR with salvage chemotherapy or immunotherapy should be considered for allogeneic SCT if they have not had a prior allogeneic SCT.[57] If relapse occurs after allogeneic SCT, a second allogeneic SCT and/or donor lymphocyte infusion can be considered in selected patients.

See local specialist protocol for dosing guidelines.

Primary options

blinatumomab

OR

inotuzumab ozogamicin

OR

tisagenlecleucel

OR

brexucabtagene autoleucel

Plus – CNS prophylaxis or treatment

Back
ONGOING
|
relapsed or refractory disease
Plus – 

CNS prophylaxis or treatment

Treatment recommended for ALL patients in selected patient group

All patients should receive CNS-directed prophylaxis or CNS-directed treatment (if CNS disease is detected) at every stage of treatment.

Patients can develop a CNS relapse despite receiving CNS prophylaxis, though this generally develops after completion of the treatment course.[67]

CNS involvement can lead to severe neurologic morbidity (e.g., cranial nerve palsies), and is a major obstacle to cure, accounting for up to 40% of initial relapses in clinical trials.[82][83][84]​ Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic stem cell transplantation (SCT).[59][69]

CNS-directed prophylaxis consists of salvage therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[52][57][126]​ Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[57]​ The specific timing, frequency, and agents used will vary depending on the treatment protocol.

Intraventricular therapy via an Ommaya reservoir should be considered if the intrathecal route is not possible.

If CNS disease is present, the recommended treatment regimen is often similar to the prophylactic regimen except the frequency of intrathecal injections may be increased (e.g., twice-weekly).

Potential adverse effects of CNS prophylaxis or treatment include acute or chronic neurotoxicity presenting as pyrexia, arachnoiditis, leukoencephalopathy, and milder subclinical CNS dysfunctions.[52][126]

Cranial or craniospinal irradiation is effective at preventing and treating CNS disease but can lead to severe adverse effects, such as neurocognitive dysfunction and secondary malignancies. Currently, it is usually reserved for treatment of overt CNS disease at diagnosis or relapse, or as prophylaxis in certain high-risk patients, or as part of a clinical trial.​[69]​​[127]

See local specialist protocol for dosing guidelines.

Primary options

Intrathecal therapy

methotrexate

OR

Triple intrathecal therapy

methotrexate

and

cytarabine

and

hydrocortisone sodium succinate

Plus – supportive care

Back
ONGOING
|
relapsed or refractory disease
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 the following complications.

Tumor lysis syndrome (TLS): an oncologic emergency. Use vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricemic agents (e.g., allopurinol or rasburicase) to prevent or treat TLS. TLS is characterized by hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and/or elevated serum lactate dehydrogenase, which can occur following chemotherapy (or spontaneously in rare cases), particularly if WBC count (tumor burden) is high. TLS can lead to cardiac arrhythmias, seizures, acute renal failure, and death, if untreated. See Tumor lysis syndrome.

Infections and febrile neutropenia: use antibiotics, antifungals, and antivirals to prevent or treat infections and febrile neutropenia.[56][155][156][157][158] [ Cochrane Clinical Answers logo ] [ Cochrane Clinical Answers logo ] Risk of infection is greatest following induction chemotherapy when neutropenia is profound and prolonged. Febrile neutropenia is an oncologic emergency. Mortality rate associated with febrile neutropenia in hospitalized patients with leukemia is reported to be approximately 14%.[159]​ Use of granulocyte colony-stimulating factors (G-CSFs; e.g., filgrastim, pegfilgrastim) to prevent febrile neutropenia is recommended during myelosuppressive therapy or as directed by the treatment protocol.[57][160] See Febrile neutropenia.

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[161][162] [ Cochrane Clinical Answers logo ] ​ Risk of bleeding complications is highest during induction therapy due to bone marrow suppression. Blood products should be irradiated, leukocyte-depleted, and cytomegalovirus-negative.[57]

Severe thrombocytopenia: use norethindrone (or a similar drug) in female patients of menstruating age to suppress menses.

Cardiotoxicity: use of dexrazoxane with chemotherapy to prevent cardiotoxicity (e.g., when cumulative dose of doxorubicin is ≥300 mg/m²), though experience with this agent in adults is limited.[163]

Oral mucositis: mouth care should be initiated to minimize oral mucositis.

Symptomatic leukostasis (hyperleukocytosis): leukapheresis may be considered in patients with symptomatic leukostasis prior to initiation of induction therapy. Systemic therapy (e.g., cytarabine, hydroxyurea, and/or corticosteroids) can also achieve urgent cytoreduction in this situation.

Fertility counseling and fertility preservation should be discussed with all patients. Fertility preservation for male patients includes semen cryopreservation postpuberty. Options for female patients are limited and merit discussion with the fertility center. There will typically be insufficient time to stimulate oocyte production to allow oocyte or embryo (if a partner is available) cryopreservation. Furthermore, cryopreserved ovarian tissue from female patients with ALL can harbor malignant cells, which may cause disease recurrence when reimplanted.[164]

Consider – tyrosine kinase inhibitor (TKI)

Back
ONGOING
|
relapsed or refractory disease
|
with Ph+ B-ALL
Consider – 

tyrosine kinase inhibitor (TKI)

Treatment recommended for SOME patients in selected patient group

An alternative TKI (different to the one used for induction therapy) can be added to salvage chemotherapy or used alone in patients with relapsed or refractory Ph+ B-ALL, based on ABL1 kinase domain mutational analysis.[57]

TKIs are given continuously until relapse or intolerance. If one TKI fails or is intolerable, another TKI should be tried.

TKIs target the BCR::ABL fusion protein associated with the Philadelphia chromosome.

Ponatinib is the only TKI that is effective in those harboring the T315I mutation in the ABL kinase domain. In patients with newly diagnosed Ph+ ALL, ponatinib plus multiagent therapy appears to be associated with improved outcomes (e.g., complete molecular response, measurable residual disease [MRD], overall survival) compared with earlier generation TKIs plus multiagent therapy.[113][114]​ 

Due to the risk of serious adverse events (e.g., severe cardiovascular events, hepatotoxicity, and posterior reversible encephalopathy syndrome), ponatinib should be used cautiously in patients with associated comorbidities. Ponatinib should be interrupted immediately if serious adverse events occur, and a decision to restart should be guided by a benefit-risk assessment.

For patients undergoing allogeneic SCT, the National Comprehensive Cancer Network (NCCN) recommends that TKI therapy should be resumed as soon as feasible post-transplant and continued for at least 2 years in patients with Ph+ B-ALL.[57] A European expert panel recommends continuing TKI therapy until 12 months of continuous MRD negativity is achieved post-transplant (for patients in CR1).[136]​ The benefits of post-transplant TKI therapy in patients with Ph+ B-ALL are unclear due to limited evidence from randomized studies; however, some data suggest improved overall survival, especially in MRD-positive patients.[136][137]​​

See local specialist protocol for dosing guidelines.

Primary options

imatinib

OR

dasatinib

OR

bosutinib

OR

nilotinib

OR

ponatinib

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