Approach

The management approach discusses treatment for adolescents and adults with acute lymphoblastic leukemia (ALL). Care should be taken to ensure that young adults are managed in age-appropriate facilities. Treatment of pediatric ALL is not covered in this topic.

Patients should be managed by a multidisciplinary team that is experienced in managing ALL (including clinical nurse specialists, hematologists, pathologists). Treatment decisions should involve the patient.

The goals of therapy are to:

  • Achieve normal hematopoiesis

  • Prevent the emergence of resistant subclones

  • Prevent disease progression to new sites (e.g., central nervous system [CNS])

  • Eliminate measurable residual disease (MRD)

  • Maintain long-term remission and improve survival

Treatment for ALL includes the use of multiagent therapy (e.g., chemotherapy, corticosteroids, asparaginase) in three treatment phases: induction, consolidation, and maintenance. Urgent chemotherapy is indicated in cases where there is advanced and complicated disease (e.g., hyperleukocytosis, large mediastinal mass).

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

Allogeneic stem cell transplantation (SCT) may be considered for consolidation therapy in selected patients (depending on donor availability, depth of remission, comorbidities), such as those at high risk.[57][76]​​

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).

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

Risk stratification

Required to select high-risk patients for novel consolidation therapy and potential allogeneic SCT to improve relapse-free survival.

Patients can be identified as high risk based on the following clinical and biologic factors:[57][77][78]​​[79][80][81]​​

  • Age: adults ages >35 years are considered high risk, although the impact of age is a continuous variable.

  • White blood cell (WBC) count at presentation: a continuous variable; >30,000/microliter for B-ALL and >100,000/microliter for T-ALL are considered high risk for adults.

  • Cytogenetic and molecular abnormalities associated with poorer outcomes (e.g., KMT2A rearrangements; see Diagnostic criteria​​).

  • Immunophenotypic subtype: CD20 expression is associated with a poor prognosis.

  • Response to induction therapy: patients receiving induction therapy who do not achieve a complete remission (CR) or who respond poorly are considered high risk.

  • Presence of MRD (e.g., ≥0.01%) following induction therapy: persistent MRD after induction has been found to be associated with poorer outcomes.

Risk stratification: CNS involvement

CNS involvement occurs in 5% to 7% of patients at diagnosis; incidence is higher in patients with T-ALL (8%) and mature B-ALL (Burkitt lymphoma/leukemia, 13%).[50][51][52][53][54] 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]

Studies have shown that use of intensive regimens in patients with CNS involvement at diagnosis results in similar outcomes (i.e., CR, disease-free survival, and overall survival) to patients without CNS involvement at diagnosis, particularly among adults.[50][51][85][86][87][88]​ Outcomes are, however, often poor in patients with CNS relapse (median overall survival <1 year).[89] Patients with CNS involvement (particularly CNS relapse) usually warrant consideration for postremission allogeneic SCT.[59][69]

Induction therapy

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

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]

Induction therapy: multiagent therapy

The standard backbone for induction is a corticosteroid (e.g., prednisone, dexamethasone) and chemotherapy agents (e.g., cyclophosphamide, vincristine, and an anthracycline [doxorubicin, daunorubicin, or idarubicin]).[90][91][92]​​ Other drugs (e.g., methotrexate, cytarabine, mercaptopurine, nelarabine) may be added to intensify the regimen.[93]

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]

​Multiagent therapy results in a CR rate of approximately 80% in adult ALL (MRD negative rate is lower), but only 40% to 60% can expect a cure.[5][76][99][100][101]

Mortality is reported in up to 10% of adult patients during induction therapy.[87][102]​​ More than two-thirds of deaths are caused by infection, and this percentage increases with increasing patient age.

Induction therapy: tyrosine kinase inhibitor (TKI)

TKIs (e.g., imatinib, dasatinib, bosutinib, nilotinib, ponatinib) target the BCR::ABL fusion protein associated with the Philadelphia chromosome.[103][104][105][106][107][108][109][110][111]​​ Patients with Philadelphia chromosome positive (Ph+) B-ALL should be treated with a TKI, 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.

Induction therapy: immunotherapy

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).

Induction therapy: Philadelphia chromosome positive (Ph+) B-ALL

A TKI combined with multiagent therapy or a corticosteroid should be used for induction therapy in patients with Ph+ B-ALL. High- or moderate-intensity regimens are preferred for adolescents and adults ages <65 years. Older adults (age ≥65 years) or those with significant comorbidities can be considered for low-intensity regimens.

Induction therapy regimens for Ph+ B-ALL include (ordered from high to low intensity):[57]

  • 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)

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.[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.

Induction therapy: Philadelphia chromosome negative (Ph-negative) B-ALL and T-ALL

Multiagent therapy should be used for induction therapy in patients with Ph-negative B-ALL and those with T-ALL. Intense pediatric-inspired protocols are preferred for adolescents and young adults (i.e., age <40 years).[57][92][115]​​ Pediatric-inspired protocols generally have larger cumulative doses of nonmyelosuppressive drugs such as corticosteroids, vincristine, and asparaginase; longer and more intense CNS-directed therapy; and a lower tendency for allogeneic SCT in first remission. Older adults (age ≥65 years) or those with significant comorbidities may receive multiagent therapy with dose modifications, or palliative corticosteroids.

Induction therapy regimens for Ph-negative B-ALL and T-ALL include:[57] 

  • 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])

Induction therapy: patients with high leukemic burden

A cautious cell reduction phase may be considered before induction therapy for patients with a high leukemic burden (i.e., WBC >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 (TLS).[53][90]​​ See Tumor lysis syndrome.

Induction therapy: MRD assessment

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.

Consolidation therapy

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

Consolidation is achieved with the use of dose-intense multiagent therapy (and continuation of TKI therapy in patients with Ph+ B-ALL). 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]

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]​ 

Consolidation therapy: immunotherapy

Patients with CD20+ Ph-negative B-ALL can be treated with rituximab in addition to consolidation therapy.[112]

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] 

Maintenance therapy

The third phase of treatment. The goal of maintenance therapy is to eliminate MRD and maintain long-term remission.

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

Maintenance therapy is recommended for all subtypes of ALL other than 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]

Maintenance therapy: 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]

Patients with Ph+ B-ALL who are undergoing maintenance therapy should continue TKI therapy in addition to the maintenance regimen. The optimal duration of TKI therapy in this setting is unclear as late molecular relapses can occur following discontinuation of maintenance TKI.[125]

CNS disease: prevention and treatment

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-directed prophylaxis consists of induction, consolidation, maintenance, or 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]

CNS disease: radiation therapy

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]​​​​

Allogeneic stem cell transplantation (SCT)

Allogeneic SCT (from a matched sibling donor or matched unrelated donor) is recommended for patients with Ph+ B-ALL in 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 TKI.[105] In one 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]

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]

Allogeneic SCT: post-transplant TKI therapy

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]​​​ 

Relapsed or refractory disease

Patients who do not achieve a 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]

Relapsed or refractory disease: immunotherapy

Antigen-specific immunotherapies are approved for patients with relapsed or refractory B-ALL, but the optimal sequence is unknown.[142]

  • Blinatumomab: a bispecific CD19-directed CD3 T-cell engager. Demonstrated longer overall survival compared with chemotherapy in a phase 3 study of adults with relapsed or refractory B-ALL (7.7 months vs. 4.0 months).[143] Blinatumomab was superior to multiagent chemotherapy as part of consolidation therapy for children with B-ALL in first relapse.[144][145]​ In one phase 2 trial, blinatumomab demonstrated significant activity against chemorefractory MRD.[122]

  • Inotuzumab ozogamicin: a CD22-targeted humanized monoclonal antibody conjugated to the cytotoxic agent calicheamicin. Demonstrated longer progression-free survival (5.0 months vs. 1.8 months) and overall survival (7.7 months vs. 6.7 months) compared with standard intensive chemotherapy in a phase 3 study of adults with relapsed or refractory B-ALL.[146]

  • Tisagenlecleucel: a CD19-targeted CAR T-cell immunotherapy. 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. In one phase 2 study, this agent demonstrated a 3-month remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-ALL.[147]

  • Brexucabtagene autoleucel: a CD19-targeted CAR T-cell immunotherapy. Approved for use in adults with relapsed or refractory B-ALL, but only through a REMS program. In one phase 2 trial of adults with relapsed or refractory B-ALL, 71% (31/55) who received brexucabtagene autoleucel achieved a CR at median follow-up of 16.4 months.[148]

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.

Relapsed or refractory disease: TKI therapy

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]

Relapsed or refractory disease: allogeneic SCT

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.

Supportive care

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 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.

Supportive care: fertility counseling

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]

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