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

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

induction 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.

A tyrosine kinase inhibitor (TKI; e.g., imatinib, dasatinib, bosutinib, nilotinib, ponatinib) combined with multiagent therapy, or a corticosteroid, or blinatumomab (a bispecific T-cell engager that targets CD19) should be used for induction therapy in patients with Philadelphia chromosome positive (Ph+) B-ALL.

Induction therapy regimens for Ph+ B-ALL include (ordered from high to low intensity): TKI plus cyclophosphamide, cytarabine, dexamethasone, doxorubicin, mercaptopurine, pegaspargase, thioguanine, and vincristine (EsPhALL regimen); TKI plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and dose-adjusted cytarabine (dose-adjusted hyper-CVAD regimen); TKI plus cyclophosphamide, daunorubicin, dexamethasone, and vincristine (CALGB 10701 regimen); TKI plus cyclophosphamide, dexamethasone, and vincristine (EWALL regimen); TKI plus vincristine and dexamethasone; TKI plus a corticosteroid (e.g., prednisone, methylprednisolone, dexamethasone); TKI plus blinatumomab (requires cytoreduction to white blood cell [WBC] count <10,000/microliter prior to initiation; for example, with TKI plus a corticosteroid).[60]

The EsPhALL regimen is only recommended for adolescents and young adults without substantial comorbidities.[60] Low-intensity regimens (e.g., a TKI plus a corticosteroid) may be more suitable for older adults (age ≥65 years) with substantial comorbidities.[60]

Asparaginase is commonly added to induction therapy (for all ALL subtypes, but more commonly in Ph-negative ALL), particularly in adolescents and young adults (age <40 years).[124] Pegaspargase is typically recommended as the asparaginase of choice. Calaspargase pegol may be preferred in patients age ≤21 years for more sustained asparaginase activity. Asparaginase Erwinia chrysanthemi (recombinant) should be used in patients who develop sensitivity to pegaspargase or calaspargase pegol.[60]

TKIs target the BCR::ABL fusion protein associated with the Philadelphia chromosome, and they should be given continuously to patients with Ph+ B-ALL 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.[117][118]​​ 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., WBC count >100,000/microliter).[127][128]​​​ This may be achieved with cytarabine, hydroxyurea, and/or corticosteroids.

Patients with a high leukemic burden should be closely monitored for tumor lysis syndrome.[57][100]​​​ 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.[60]

MRD assessment should be performed 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).[129]​ 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 + EsPhALL regimen

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

cyclophosphamide

and

cytarabine

and

dexamethasone

and

doxorubicin

and

mercaptopurine

and

thioguanine

and

vincristine

-- AND --

pegaspargase

or

calaspargase pegol

or

asparaginase erwinia chrysanthemi (recombinant)

OR

TKI + dose-adjusted hyper-CVAD regimen

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

cyclophosphamide

and

vincristine

and

doxorubicin

and

dexamethasone

and

methotrexate

and

cytarabine

OR

TKI + CALGB 10701 regimen

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

cyclophosphamide

and

daunorubicin

and

dexamethasone

and

vincristine

OR

TKI + EWALL regimen

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

cyclophosphamide

and

dexamethasone

and

vincristine

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

OR

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

blinatumomab

Plus – CNS prophylaxis or treatment

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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.[72]

CNS-directed prophylaxis consists of induction therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[9][60][136]​​ Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[60] 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.[9][136]

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.​[74][137]

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

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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.[62][163][164][165][166] [ 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%.[167]​ 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.[60][168]​ See Febrile neutropenia. 

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[169][170] [ 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.[60]

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.[171]

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.[172]

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

1st line – induction therapy

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

induction 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 regimens or inotuzumab ozogamicin (a CD22-targeted humanized monoclonal antibody conjugated to the cytotoxic agent calicheamicin)-based regimens should be used for induction therapy in patients with Philadelphia chromosome negative (Ph-negative) B-ALL.

Multiagent therapy regimens should be used for induction therapy in patients with T-ALL.

Induction therapy regimens for Ph-negative B-ALL and T-ALL include: daunorubicin, vincristine, prednisone, and pegaspargase (CALGB 10403 and Linker 4-drug regimens); doxorubicin, vincristine, prednisone, methotrexate, and pegaspargase (DFCI ALL regimen); daunorubicin, vincristine, prednisone, pegaspargase, and cyclophosphamide (GRAALL-2005, dose-adjusted CALGB 8811 Larson, CALGB 9111, and PETHEMA ALL-96 regimens); hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with high-dose methotrexate and dose-adjusted cytarabine (dose-adjusted hyper-CVAD regimen); cyclophosphamide, cytarabine, daunorubicin, mercaptopurine, pegaspargase, prednisone, and vincristine (USC/MSKCC ALL regimen); mercaptopurine, vincristine, methotrexate, and prednisone (POMP regimen); vincristine plus prednisone.[60]

Other induction therapy regimens for Ph-negative B-ALL include: cyclophosphamide, cytarabine, daunorubicin, dexamethasone, mercaptopurine, pegaspargase, and vincristine (ECOG1910 regimen); hyperfractionated cyclophosphamide, vincristine, dexamethasone, and inotuzumab ozogamicin alternating with cytarabine, methotrexate, and inotuzumab ozogamicin (inotuzumab ozogamicin plus mini-hyper-CVD regimen); inotuzumab ozogamicin with or without dexamethasone.[60] 

The list of regimens is not exhaustive; consult local guidelines for recommended regimens.

Intense pediatric-inspired protocols (e.g., CALGB 10403, DFCI ALL, PETHEMA ALL-96, GRAALL-2005, and USC/MSKCC ALL regimens) are preferred for adolescents and young adults (i.e., age <40 years).[60][102][125] Pediatric-inspired protocols generally have larger cumulative doses of nonmyelosuppressive drugs such as corticosteroids, vincristine, and pegaspargase; longer and more intense CNS-directed therapy; and a lower tendency for allogeneic stem cell transplantation (SCT) in first remission. Older adults (age ≥65 years) or those with significant comorbidities may receive multiagent therapy with dose modifications, or inotuzumab ozogamicin alone (for those with Ph-negative B-ALL), or palliative corticosteroids.[60] 

Asparaginase is commonly added to induction therapy (for all ALL subtypes, but more commonly in Ph-negative B-ALL), particularly in adolescents and young adults (age <40 years).[124] Pegaspargase is typically recommended as the asparaginase of choice. Calaspargase pegol may be preferred in patients age ≤21 years for more sustained asparaginase activity. Asparaginase Erwinia chrysanthemi (recombinant) should be used in patients who develop sensitivity to pegaspargase or calaspargase pegol.[60]

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).[127][128]​ This may be achieved with cytarabine, hydroxyurea, and/or corticosteroids.

Patients with a high leukemic burden should be closely monitored for tumor lysis syndrome.[57][100]​ 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.[60]

Measurable residual disease (MRD) assessment should be performed 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.[129]​ 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 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, dose-adjusted CALGB 8811 Larson, CALGB 9111, and PETHEMA ALL-96 regimens

daunorubicin

and

vincristine

and

prednisone

and

cyclophosphamide

-- AND --

pegaspargase

or

calaspargase pegol

or

asparaginase erwinia chrysanthemi (recombinant)

OR

Dose-adjusted hyper-CVAD regimen

cyclophosphamide

and

vincristine

and

doxorubicin

and

dexamethasone

and

methotrexate

and

cytarabine

OR

USC/MSKCC ALL regimen

cyclophosphamide

and

cytarabine

and

daunorubicin

and

mercaptopurine

and

prednisone

and

vincristine

-- AND --

pegaspargase

or

calaspargase pegol

or

asparaginase erwinia chrysanthemi (recombinant)

OR

POMP regimen

mercaptopurine

and

vincristine

and

methotrexate

and

prednisone

OR

vincristine

and

prednisone

OR

ECOG1910 regimen

cyclophosphamide

and

cytarabine

and

daunorubicin

and

dexamethasone

and

mercaptopurine

and

vincristine

-- AND --

pegaspargase

or

calaspargase pegol

or

asparaginase erwinia chrysanthemi (recombinant)

OR

Inotuzumab ozogamicin plus mini-hyper-CVD regimen

cyclophosphamide

and

vincristine

and

dexamethasone

and

inotuzumab ozogamicin

and

cytarabine

and

methotrexate

OR

inotuzumab ozogamicin

and

dexamethasone

OR

inotuzumab ozogamicin

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.[72]

CNS-directed prophylaxis consists of induction therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[9][60][136]​ Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[60] 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.[9][136]

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.[74][137]​​ 

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.[62][163][164][165][166] [ 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%.[167]​ 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.[60][168] See Febrile neutropenia. 

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[169][170] [ 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.[60]

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.[171]

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.[172]

Plus – rituximab

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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

Rituximab (an anti-CD20 monoclonal antibody) can be added to induction therapy regimens for patients with CD20+ Ph-negative B-ALL.

In one randomized study, rituximab improved event-free survival in patients with CD20+ Ph-negative B-ALL, especially young adults.[126]​ 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: Ph+ B-ALL

1st line – consolidation therapy

Back
ONGOING
|
complete remission: Ph+ B-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 required to select high-risk patients for systemic consolidation therapy and potential consolidation with allogeneic stem cell transplantation (SCT).

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+ and early T-cell precursor [ETP]-ALL subtype); 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.[60][86][87][88][89][90]​​​​​​​​​​[91]​​​

Consolidation therapy options for patients with Philadelphia chromosome positive (Ph+) B-ALL include: blinatumomab with or without a tyrosine kinase inhibitor (TKI), such as imatinib, dasatinib, bosutinib, nilotinib, or ponatinib (if MRD is persistent or rising); continuation of multiagent therapy (or corticosteroid) plus a TKI (if MRD is persistent, rising, or negative); inotuzumab ozogamicin with or without a TKI (if MRD is persistent or rising); blinatumomab plus a TKI (if MRD is negative); TKI alone (if MRD is persistent, rising, or negative, and patient is unfit for additional therapies).[60]

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, MRD, overall survival) compared with earlier-generation TKIs plus multiagent therapy.[117][118]​ 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.

Allogeneic SCT (from a matched sibling donor or matched unrelated donor) is recommended for patients with Ph+ B-ALL in first complete remission (e.g., as consolidation therapy in lieu of systemic therapy), if eligible (e.g., based on age, comorbidities, performance status).[129][130][131] 

Deferring allogeneic SCT (and continuing systemic therapy for consolidation and maintenance) may be an option in some patients with Ph+ B-ALL.[110][138] 

Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic SCT.[74][82]​​

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.[60][140][141]

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 sinusoidal obstruction syndrome. See Graft versus host disease.

For patients undergoing allogeneic SCT, National Comprehensive Cancer Network (NCCN) guidelines recommend 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.[60] A European expert panel recommends continuing TKI therapy until 12 months of continuous MRD negativity is achieved post-transplant (for patients in CR1).[142]​

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.[142][143]​

See local specialist protocol for regimens and dosing guidelines.

Consider – maintenance therapy

Back
ONGOING
|
complete remission: Ph+ B-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 who do not undergo consolidation with allogeneic stem cell transplantation (SCT).[60]

Maintenance therapy is recommended for all subtypes of ALL other than mature B-ALL (Burkitt lymphoma/leukemia).[60] Patients with mature B-ALL usually achieve long-term remission following early intensive therapy, and most relapses occur early (within 1 year).[60][132]

Standard maintenance regimen usually includes mercaptopurine, vincristine, methotrexate, and prednisone (POMP maintenance regimen) 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.[133]

Thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) phenotype may be assessed at diagnosis to allow individualized dosing of mercaptopurine.[76]

Patients with Philadelphia chromosome positive (Ph+) B-ALL who are undergoing maintenance therapy should continue tyrosine kinase inhibitor (TKI) therapy (e.g., imatinib, dasatinib, bosutinib, nilotinib, or ponatinib) in addition to the POMP maintenance regimen.[60] 

A TKI alone can be considered for maintenance therapy in patients with Ph+ B-ALL who previously received blinatumomab plus a TKI and are unfit for additional therapies.[60] The optimal duration of TKI therapy in the maintenance setting is unclear as late molecular relapses can occur following discontinuation of maintenance TKI.[134] 

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, MRD, overall survival) compared with earlier-generation TKIs plus multiagent therapy.[117][118]​ 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.

See local specialist protocol for dosing guidelines.

Primary options

TKI + POMP maintenance regimen

imatinib

or

dasatinib

or

bosutinib

or

nilotinib

or

ponatinib

-- AND --

mercaptopurine

and

vincristine

and

methotrexate

and

prednisone

OR

imatinib

OR

dasatinib

OR

bosutinib

OR

nilotinib

OR

ponatinib

Plus – CNS prophylaxis or treatment

Back
ONGOING
|
complete remission: 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.[72]

CNS-directed prophylaxis consists of consolidation therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[9][60][136]​ Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[60] 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.[9][136]

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.[74][137]

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
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.[62][163][164][165][166] [ 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%.[167] 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.[60][168] See Febrile neutropenia.

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[169][170] [ 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.[60]

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.[171]

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.[172]

complete remission: Ph-negative B-ALL

1st line – consolidation therapy

Back
ONGOING
|
complete remission: Ph-negative B-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 required to select high-risk patients for systemic consolidation therapy and potential consolidation with allogeneic stem cell transplantation (SCT).

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+ and early T-cell precursor [ETP]-ALL subtype); 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.[60]​​​[86]​​[87][88][89][90][91]​​ 

Consolidation therapy options for patients with Philadelphia chromosome negative (Ph-negative) B-ALL include: blinatumomab (if MRD is persistent, rising, negative, or unavailable); inotuzumab ozogamicin (if MRD is persistent or rising); continuation of multiagent therapy alternating with blinatumomab (if MRD is negative or unavailable).[60] 

Allogeneic SCT (from a matched sibling donor or matched unrelated donor) is recommended for patients with high-risk Ph-negative B-ALL in first complete remission (e.g., as consolidation therapy in lieu of systemic therapy), if eligible.[129][131] 

There is some evidence supporting the use of allogeneic SCT in patients with standard-risk disease in first complete remission, but this is controversial and not standard practice.[131][139]

Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic SCT.[74][82]​​ 

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.[60][140][141] 

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 sinusoidal obstruction syndrome. See Graft versus host disease.

See local specialist protocol for regimens and dosing guidelines.

Consider – maintenance therapy

Back
ONGOING
|
complete remission: Ph-negative B-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 who do not undergo consolidation with allogeneic stem cell transplantation (SCT).[60] 

Maintenance therapy is recommended for all subtypes of ALL other than mature B-ALL (Burkitt lymphoma/leukemia).[60] Patients with mature B-ALL usually achieve long-term remission following early intensive therapy, and most relapses occur early (within 1 year).[60][132] 

Standard maintenance regimen usually includes mercaptopurine, vincristine, methotrexate, and prednisone (POMP maintenance regimen) 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.[133]

Thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) phenotype may be assessed at diagnosis to allow individualized dosing of mercaptopurine.[76] 

Patients with Ph-negative B-ALL can be considered for maintenance therapy with: POMP maintenance regimen; or blinatumomab alternating with POMP maintenance regimen (if induced with inotuzumab ozogamicin plus mini-hyper-CVD plus blinatumomab regimen, or dose-adjusted hyper-CVAD plus blinatumomab regimen).[60][123][135]

See local specialist protocol for dosing guidelines​.

Primary options

POMP maintenance regimen

mercaptopurine

and

vincristine

and

methotrexate

and

prednisone

OR

Blinatumomab + POMP maintenance regimen

blinatumomab

and

mercaptopurine

and

vincristine

and

methotrexate

and

prednisone

Plus – CNS prophylaxis or treatment

Back
ONGOING
|
complete remission: Ph-negative 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.[72]

CNS-directed prophylaxis consists of consolidation therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[9][60][136] Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[60] 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.[9][136]

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.[74][137]

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-negative 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.[62][163][164][165][166] [ 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%.[167] 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.[60][168] See Febrile neutropenia.

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[169][170] [ 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.[60] 

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.[171] 

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.[172]

Consider – rituximab (with consolidation therapy)

Back
ONGOING
|
complete remission: Ph-negative B-ALL
|
with CD20+ Ph-negative B-ALL
Consider – 

rituximab (with consolidation therapy)

Treatment recommended for SOME patients in selected patient group

Rituximab (an anti-CD20 monoclonal antibody) can be added to consolidation therapy regimens for patients with CD20+ Ph-negative B-ALL.

In one randomized study, rituximab improved event-free survival in patients with CD20+ Ph-negative B-ALL, especially young adults.[126]​​ In this study, rituximab was given during all treatment phases (including maintenance).

See local specialist protocol for dosing guidelines.

Primary options

rituximab

complete remission: T-ALL

1st line – consolidation therapy

Back
ONGOING
|
complete remission: 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 required to select high-risk patients for systemic consolidation therapy and potential consolidation with allogeneic stem cell transplantation (SCT).

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+ and early T-cell precursor [ETP]-ALL subtype); 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.[60][86]​​[87]​​​[88][89][90]​​​​​[91]​​

Consolidation therapy for patients with T-ALL is continuation of multiagent therapy.[60] 

Allogeneic SCT (from a matched sibling donor or matched unrelated donor) is recommended for patients with high-risk T-ALL in first complete remission (e.g., as consolidation therapy in lieu of further systemic therapy), if eligible.[129][131] 

There is some evidence supporting the use of allogeneic SCT in patients with standard-risk disease in first complete remission, but this is controversial and not standard practice.[131][139] 

Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic SCT.[74][82]​​ 

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.[60][140][141]

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 sinusoidal obstruction syndrome. See Graft versus host disease.

See local specialist protocol for regimens and dosing guidelines.

Consider – maintenance therapy

Back
ONGOING
|
complete remission: 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 who do not undergo consolidative allogeneic stem cell transplantation (SCT).[60] 

Maintenance therapy is recommended for all subtypes of ALL other than mature B-ALL (Burkitt lymphoma/leukemia).[60] Patients with mature B-ALL usually achieve long-term remission following early intensive therapy, and most relapses occur early (within 1 year).[60][132] 

Standard maintenance regimen usually includes mercaptopurine, vincristine, methotrexate, and prednisone (POMP maintenance regimen) 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.[133] 

Thiopurine methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) phenotype may be assessed at diagnosis to allow individualized dosing of mercaptopurine.[76] 

See local specialist protocol for dosing guidelines.

Primary options

POMP maintenance regimen

mercaptopurine

and

vincristine

and

methotrexate

and

prednisone

Plus – CNS prophylaxis or treatment

Back
ONGOING
|
complete remission: 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.[72] 

CNS-directed prophylaxis consists of consolidation therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[9][60][136] Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[60] 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.[9][136] 

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.[74][137] 

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: 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.[62][163][164][165][166] [ 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%.[167] 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.[60][168] See Febrile neutropenia.

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[169][170] [ 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.[60]

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.[171]

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.[172]

relapsed or refractory disease

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

Back
ONGOING
|
relapsed or refractory disease
1st line – 

salvage chemotherapy or immunotherapy or targeted therapy ± 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.[144][145][146][147]​ If relapse occurs ≥3 years from diagnosis (i.e., late relapse) in patients with Philadelphia negative (Ph-negative) B-ALL and T-ALL, the same regimen used for induction therapy can be considered for salvage therapy.[60]

Immunotherapy and targeted therapies are approved for patients with relapsed or refractory ALL, but the optimal sequence is unknown.[148]

Blinatumomab (a CD19-directed CD3 T-cell engager) is approved for relapsed or refractory CD19-positive B-ALL.​[149][150][151][152]

Inotuzumab ozogamicin (a CD22-targeted humanized monoclonal antibody conjugated to the cytotoxic agent calicheamicin) is approved for relapsed or refractory CD22-positive B-ALL.[153] 

Tisagenlecleucel (a CD19-targeted chimeric antigen receptor [CAR] T-cell immunotherapy) is approved for use in patients up to 25 years of age with B-ALL that is refractory or in second or later relapse, but only through a Risk Evaluation and Mitigation Strategy (REMS) program.[154]

Brexucabtagene autoleucel (a CD19-targeted CAR T-cell immunotherapy) is approved for use in adults with relapsed or refractory B-ALL, but only through a REMS program.[79]

Obecabtagene autoleucel (a CD19-targeted CAR T-cell immunotherapy) is approved for use in adults with relapsed or refractory B-ALL.[155]​​ 

Revumenib (a menin inhibitor) is approved for use in patients with relapsed or refractory acute leukemia with a KMT2A translocation.[156]​​

Immunotherapies and targeted therapies are associated with serious adverse effects. Severe hepatotoxicity (including sinusoidal obstruction syndrome) may occur with inotuzumab ozogamicin.[153][157][158]​​​ Cytokine release syndrome (CRS) and neurologic toxicity may occur with blinatumomab and CD19-targeted CAR T-cell immunotherapies.[79][149][154][155]​​​​​[159][160]​​​​​ Tocilizumab is recommended for the management of patients with prolonged or severe CAR T-cell-associated CRS.[161]​ T-cell malignancies may also occur following treatment with CD19-targeted CAR T-cell immunotherapies.[162]​ Some cases have occurred weeks after treatment, and some have been fatal. Fatal or life-threatening differentiation syndrome may occur with revumenib.[156]​​

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.[60] 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

OR

obecabtagene autoleucel

OR

revumenib

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.[72]

CNS-directed prophylaxis consists of salvage therapy regimens augmented with intermittent intrathecal methotrexate alone or with intrathecal cytarabine and intrathecal hydrocortisone ("triple intrathecal therapy").[9][60][136]​​ Regimens often include intensive systemic therapy with high-dose cytarabine or high-dose methotrexate to ensure good blood-brain penetration.[60]​ 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.[9][136]

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.​[74]​​[137]

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.[62][163][164][165][166] [ 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%.[167]​ 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.[60][168] See Febrile neutropenia.

Bleeding: use platelet transfusions to prevent or treat bleeding complications.[169][170] [ 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.[60]

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.[171]

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.[172]

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.[60]

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.[117][118]​ 

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, National Comprehensive Cancer Network (NCCN) guidelines recommend 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.[60] A European expert panel recommends continuing TKI therapy until 12 months of continuous MRD negativity is achieved post-transplant (for patients in CR1).[142]​

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.[142][143]​​​

See local specialist protocol for dosing guidelines.

Primary options

imatinib

OR

dasatinib

OR

bosutinib

OR

nilotinib

OR

ponatinib

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