New Guidelines for Treating Acute Lymphoblastic Leukemia in Adolescents and Young Adults

Table of Contents

• Key Points
• Background: Why This Guideline Matters
• How the Guidelines Were Developed
• Understanding Recommendation Strength
• Frontline Treatment Approach
• Asparaginase Management: Dosing Strategies
• Asparaginase Management: Preventing Allergic Reactions
• Therapeutic Drug Monitoring
• Blood Clot Prevention During Treatment
• Switching Asparaginase Formulations After Allergic Reactions
• Resuming Asparaginase After Non-Allergic Toxicity
• Stem Cell Transplant in First Remission
• Adding Rituximab for CD20-Positive B-ALL
• Adding Blinatumomab for B-ALL
• Nelarabine for T-Cell Leukemia and Lymphoma
• Bortezomib for T-Cell Leukemia
• Treatment for Philadelphia Chromosome-Positive ALL
• Central Nervous System Prophylaxis
• Cranial Radiation for CNS Prophylaxis
• Approach for Minimal Residual Disease
• Good Practice Statements: Holistic Care for Young Adults
• What These Guidelines Mean for Patients
• Limitations of the Evidence
• Actionable Recommendations for Patients and Families
• Frequently Asked Questions
• Source Information

Key Points

• For adolescents and young adults with ALL, guidelines strongly recommend pediatric-inspired regimens containing asparaginase as frontline therapy, based on moderate certainty evidence.
• Allogeneic stem cell transplant is not routinely recommended in first remission, but may benefit certain high-risk patients such as those with persistent minimal residual disease.
• Targeted therapies like rituximab for CD20-positive B-ALL and blinatumomab for B-ALL are conditionally suggested, though evidence certainty is very low.
• Comprehensive supportive care is emphasized, including psychosocial, financial, fertility, and sexual health support, plus clinical trial participation.
• Persistent minimal residual disease after at least three months of therapy warrants a strong recommendation to change treatment approach, such as immunotherapy or transplant.

Background: Why This Guideline Matters

Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) represent a unique patient population. ALL is a cancer of the blood and bone marrow in which the body produces too many immature white blood cells called lymphoblasts.

Treatment regimens for AYA patients can vary significantly depending on whether they receive care in a pediatric or an adult setting. This variation creates uncertainty about the best approach to treatment.

AYA patients also have distinctive care needs, social risk factors, and disease behavior compared with other age groups. These differences mean that treatment approaches designed for children or older adults may not fully address the needs of adolescents and young adults.

The American Society of Hematology (ASH) developed these evidence-based guidelines. The guidelines support patients, clinicians, and other health care professionals in their decisions about the frontline management of ALL in AYA patients. Frontline management refers to the initial treatment given after diagnosis.

How the Guidelines Were Developed

ASH formed a multidisciplinary guideline panel to develop these recommendations. The panel included hematologists (blood cancer specialists), AYA psychosocial care specialists, pharmacists, methodologists, and patient representatives.

The panel made efforts to minimize bias from conflicts of interest among its members. An evidence review team at Brown University supported guideline development by performing systematic evidence reviews up to November 2023.

The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the grading of recommendations assessment, development, and evaluation (GRADE) approach to assess evidence and make recommendations.

The GRADE approach includes evidence-to-decision frameworks that help panels consider factors beyond just the research evidence. These factors include patient values and preferences, resource use, and feasibility. The recommendations were also subject to public comment before finalization.

The panel agreed on 15 recommendations and several good practice statements. Good practice statements endorse interventions or practices that the panel agreed have unequivocal net benefit yet may not be widely recognized or used. These statements are not based on a systematic review of available evidence, but they may be interpreted as strong recommendations.

Understanding Recommendation Strength

The guidelines use two levels of recommendation strength: strong and conditional. Understanding these levels helps patients and families interpret what the recommendations mean for their care.

Strong recommendations are expressed as "the guideline panel recommends." For strong recommendations, most individuals in a given situation would want the recommended course of action, and only a small proportion would not. Most clinicians should follow the recommended course of action, and the recommendation can be adopted as policy in most situations.

Conditional recommendations are expressed as "the guideline panel suggests." For conditional recommendations, most individuals would want the suggested course of action, but many would not. Different choices will be appropriate for individual patients, and clinicians must help each patient arrive at a management decision consistent with that patient's values and preferences.

The guidelines also use symbols to indicate certainty in the evidence. Four filled circles indicate high certainty, three filled circles indicate moderate certainty, two filled circles indicate low certainty, and one filled circle indicates very low certainty.

It may seem surprising that many recommendations are based on very low certainty evidence. This reflects the reality that ALL is a relatively rare cancer in AYA patients, making it difficult to conduct large randomized controlled trials. The panel made recommendations based on the best available evidence while acknowledging these limitations.

Frontline Treatment Approach

Recommendation 1: For adolescents and young adults with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL) or T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, the ASH guideline panel recommends pediatric-inspired regimens that contain asparaginase.

This is a strong recommendation based on moderate certainty in the evidence of effects. This represents one of the strongest recommendations in the entire guideline.

Pediatric-inspired regimens are treatment protocols originally developed for children with ALL and then adapted for use in adolescents and young adults. These regimens contain asparaginase, an enzyme that depletes a substance called asparagine that leukemia cells need to survive.

The recommendation favors pediatric-inspired regimens over more traditional adult-inspired protocols. This represents a significant shift in how AYA patients with ALL should be treated.

Patients receiving pediatric-inspired regimens require significant supportive care and close follow-up. This means more frequent clinic visits, monitoring for side effects, and management of treatment-related complications.

Asparaginase Management: Dosing Strategies

Recommendation 2: For AYAs with ALL receiving frontline pediatric-inspired regimens containing asparaginase, the ASH guideline panel suggests that empiric dose capping and dose reductions are reasonable strategies to mitigate asparaginase-induced toxicities in AYAs without evidence of adversely affecting disease outcomes.

This is a conditional recommendation based on very low certainty in the evidence of effects. The word "empiric" means these strategies are based on clinical experience rather than definitive research evidence.

The panel defines dose capping as a maximum pegylated asparaginase (PEG-Asp) dose of 3750 international units (IU). Pegylated asparaginase is a form of the drug that stays in the body longer, allowing for less frequent dosing.

The panel defines reduced dosing of PEG-Asp as any weight-based dose of less than 2500 IU/m² for individuals aged younger than 22 years. For individuals aged 22 years or older, reduced dosing means less than 2000 IU/m².

These strategies aim to reduce side effects while maintaining the anti-leukemia benefits of asparaginase. Asparaginase can cause serious side effects including allergic reactions, blood clotting problems, and pancreatic inflammation.

Asparaginase Management: Preventing Allergic Reactions

Recommendation 3: For AYAs with ALL receiving frontline pediatric-inspired regimens containing asparaginase, the ASH guideline panel recommends the use of prophylactic premedication to prevent hypersensitivity reactions.

This is a strong recommendation based on very low certainty in the evidence of effects. Hypersensitivity reactions are allergic reactions that can range from mild skin rashes to severe, life-threatening reactions.

Premedication is defined at a minimum as intravenous (IV) steroid premedication. It may also include antihistamines and/or acetaminophen. These medications are given before asparaginase to reduce the risk of allergic reactions.

This recommendation is particularly important because allergic reactions to asparaginase can lead to treatment interruptions. When patients cannot receive asparaginase, they may lose an important component of their leukemia treatment.

Therapeutic Drug Monitoring

Good Practice Statement for Recommendations 2 and 3: The panel considers it good practice to use therapeutic drug monitoring (TDM) to ensure adequate asparagine depletion when dose capping and dose reductions are undertaken.

Therapeutic drug monitoring involves measuring the levels of asparaginase activity in the blood. This helps doctors determine whether the drug is effectively depleting asparagine, which is the substance leukemia cells need to survive.

TDM should also be used in the context of premedication to determine whether hypersensitivity reactions are associated with antibody-mediated inactivation. This means the body's immune system produces antibodies that neutralize the drug, making it undetectable in the blood. TDM can also identify silent inactivation, which occurs when the drug stops working without obvious allergic symptoms.

The panel recognizes that there is some heterogeneity in the target asparaginase activity levels across studies. This means different studies have used different target levels. There is also variation in when and how levels should be monitored.

Based on pharmacokinetic and clinical outcomes data, activity levels of at least 0.1 IU/mL for at least 14 days are recommended to ensure adequate asparagine depletion. Pharmacokinetics refers to how the body processes a drug, including how quickly it is absorbed, distributed, and eliminated.

Blood Clot Prevention During Treatment

Recommendation 4: For AYAs with ALL receiving frontline pediatric-inspired regimens containing asparaginase, the ASH guideline panel recommends against the routine use of cryoprecipitate replacement or fibrinogen concentrate outside the context of active bleeding.

This is a strong recommendation based on very low certainty in the evidence of effects. Cryoprecipitate and fibrinogen concentrate are blood products that contain clotting factors. Asparaginase can lower fibrinogen levels, which might theoretically increase bleeding risk.

However, the panel recommends against routinely giving these products unless the patient is actively bleeding. This recommendation reflects evidence that low fibrinogen levels alone do not necessarily require treatment.

Recommendation 5: For AYAs with ALL receiving frontline pediatric-inspired regimens containing asparaginase, the ASH guideline panel recommends against the routine use of unfractionated heparin (UFH) for venous thromboembolism (VTE) prophylaxis.

This is a strong recommendation based on very low certainty in the evidence of effects. Venous thromboembolism refers to blood clots that form in veins, which can travel to the lungs and become life-threatening. Unfractionated heparin is a blood-thinning medication.

No Recommendation: For AYAs with ALL receiving frontline pediatric-inspired regimens containing asparaginase, the ASH guideline panel determined that the evidence is insufficient to issue a recommendation for or against routine VTE prophylaxis with low molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs).

This means the panel could not determine whether these blood thinners should be used routinely to prevent clots. Low molecular weight heparin and direct oral anticoagulants are different types of blood-thinning medications.

No Recommendation: For AYAs with ALL receiving frontline pediatric-inspired regimens containing asparaginase, the ASH guideline panel determined that the evidence is insufficient to issue a recommendation for or against routine antithrombin (AT) replacement.

Antithrombin is a natural protein that prevents blood from clotting too easily. Asparaginase can lower antithrombin levels, but whether replacing it helps prevent clots is unclear.

The panel recognizes there is uncertainty in the timing and duration of VTE prophylaxis. It is unclear whether prophylaxis should be given during induction, consolidation, or intensification phases of treatment. The optimal dosing of LMWH and targets for AT replacement are also uncertain.

The panel highlights the importance of risk models to identify patients at high risk for developing VTE. Such models could help doctors decide which patients might benefit most from preventive measures.

Switching Asparaginase Formulations After Allergic Reactions

Recommendation 6: For AYAs with ALL receiving frontline pediatric-inspired regimens containing asparaginase who develop an asparaginase-related allergic or hypersensitivity reaction with PEG-Asp, the ASH guideline panel recommends that patients switch to an Erwinia-based asparaginase formulation over discontinuation of asparaginase therapy.

This is a strong recommendation based on very low certainty in the evidence of effects. Erwinia-based asparaginase is a different form of the drug that comes from a different bacterial source. Because it has a different structure, patients who are allergic to PEG-Asp may tolerate Erwinia-based asparaginase.

The panel was unable to provide a recommendation related to desensitization. Desensitization is a procedure that gradually exposes a patient to increasing amounts of a drug to which they are allergic. The panel could not recommend for or against desensitization because of the lack of evidence comparing its effects with alternative asparaginase products.

The ASH guideline panel concluded that the benefits of switching to Erwinia-based asparaginase, such as improved survival and disease control, outweighed the drawbacks. These drawbacks include the high costs and resources required for Erwinia-based treatments.

The panel further recognizes that evidence in this area is evolving. This recommendation may change as new data become available.

Resuming Asparaginase After Non-Allergic Toxicity

No Recommendation: For AYAs with ALL receiving frontline pediatric-inspired regimens containing asparaginase who have a non-hypersensitivity asparaginase-related toxicity, the ASH guideline panel determined that the evidence is insufficient to issue a recommendation on resuming asparaginase therapy.

Non-hypersensitivity toxicities are side effects that are not allergic reactions. These can include pancreatitis (inflammation of the pancreas), blood clotting problems, and liver toxicity. The panel could not determine whether it is safe or beneficial to resume asparaginase after these types of side effects.

Stem Cell Transplant in First Remission

Recommendation 7: For AYAs with ALL receiving frontline therapy and in first complete remission (CR1), the ASH guideline panel suggests against routinely proceeding with allogeneic hematopoietic stem cell transplantation (allo-HSCT) as consolidation.

This is a conditional recommendation based on very low certainty in the evidence of effects. Complete remission means that the leukemia is no longer detectable in the blood and bone marrow after initial treatment. Consolidation refers to additional treatment given after remission is achieved to prevent the leukemia from returning.

Allogeneic hematopoietic stem cell transplantation is a procedure in which a patient receives stem cells from a donor. These stem cells can come from a sibling, an unrelated donor, or umbilical cord blood. The transplanted cells help rebuild the patient's immune system and can attack any remaining leukemia cells.

While allo-HSCT can be curative, it also carries significant risks. These include graft-versus-host disease, in which the donor cells attack the patient's body, and serious infections due to a weakened immune system.

The panel notes that for specific high-risk subgroups, there may be a survival benefit from allo-HSCT in CR1. These subgroups include patients with persistent minimal residual disease (MRD), induction failure, and high-risk biologic subsets.

Minimal residual disease refers to small numbers of leukemia cells that remain in the body after treatment but are too few to be detected by standard tests. Induction failure means the initial treatment did not achieve remission. High-risk biologic subsets are types of leukemia with genetic features that make them more resistant to treatment.

Adding Rituximab for CD20-Positive B-ALL

Recommendation 8: For AYAs with CD20-positive B-ALL receiving frontline therapy, the ASH guideline panel suggests the addition of rituximab to standard chemotherapy.

This is a conditional recommendation based on very low certainty in the evidence of effects. CD20 is a protein found on the surface of certain white blood cells, including some leukemia cells. Rituximab is a targeted therapy that attaches to CD20 and helps the immune system destroy those cells.

The panel recognizes considerable uncertainty associated with several aspects of rituximab use. These include the optimal dosing, frequency, and timing of administration. The minimum required level of CD20 expression for rituximab to be effective is also unclear. Additionally, there is a lack of data specific to younger AYA individuals.

Adding Blinatumomab for B-ALL

Recommendation 9: For AYAs with B-ALL receiving frontline therapy, the ASH guideline panel suggests the addition of blinatumomab for those who achieve morphologic remission, regardless of MRD status.

This is a conditional recommendation based on very low certainty in the evidence of effects. Morphologic remission means that leukemia cells are no longer visible under a microscope in the bone marrow. Blinatumomab is a type of immunotherapy that helps the immune system recognize and attack leukemia cells.

The recommendation applies regardless of MRD status. This means that even patients who have no detectable MRD and those who have persistent MRD may benefit from adding blinatumomab.

The panel recognizes there are limited data using blinatumomab within conventional pediatric-inspired chemotherapy backbones in AYAs. Most studies of blinatumomab have been conducted in different treatment settings or patient populations.

The panel further recognizes the evolution of evidence in this area. This recommendation may change as new data become available.

Guidance for individuals with MRD persistence is addressed in Recommendation 15.

Nelarabine for T-Cell Leukemia and Lymphoma

No Recommendation: For AYAs with T-ALL receiving frontline therapy with all planned doses of asparaginase, including Capizzi methotrexate-based interim maintenance, the ASH guideline panel determined that the evidence is insufficient to issue a recommendation for or against the addition of nelarabine.

Nelarabine is a chemotherapy drug that is specifically active against T-cell malignancies. T-ALL is a type of ALL that affects T-cells, a type of white blood cell. Capizzi methotrexate-based interim maintenance is a specific phase of treatment that uses methotrexate.

The panel noted that incorporating nelarabine may provide benefit among subgroups of AYAs. These subgroups include those with non-early T-cell precursor (non-ETP) subtype, central nervous system 3 (CNS3) disease, and others who receive a high-dose methotrexate-based interim maintenance regimen.

Non-ETP subtype refers to a specific type of T-ALL that does not have features of early T-cell precursors. CNS3 disease means that leukemia cells have been found in the cerebrospinal fluid, which surrounds the brain and spinal cord.

Recommendation 10: For AYAs with T-LBL/LLy receiving frontline therapy, the ASH guideline panel suggests against the addition of nelarabine.

This is a conditional recommendation based on very low certainty in the evidence of effects. T-LBL/LLy is T-cell acute lymphoblastic lymphoma/leukemia, a related condition that primarily affects lymph nodes but can also involve the bone marrow.

The panel made this recommendation due to insufficient evidence demonstrating efficacy for nelarabine in these patients.

Bortezomib for T-Cell Leukemia

Recommendation 11: For AYAs with T-ALL receiving frontline therapy, the ASH guideline panel suggests against the addition of bortezomib into treatment regimens.

This is a conditional recommendation based on very low certainty in the evidence of effects. Bortezomib is a proteasome inhibitor, a type of drug that interferes with how cells break down proteins. It is used in several other types of cancer.

The panel noted that incorporating bortezomib may provide benefit among the youngest adolescents of the AYA population. This suggests that age may be an important factor in determining whether bortezomib is beneficial.

No Recommendation: For AYAs with T-LBL/LLy, the ASH guideline panel determined the evidence is insufficient to recommend for or against addition of bortezomib.

Treatment for Philadelphia Chromosome-Positive ALL

Recommendation 12: For AYAs with Philadelphia chromosome-positive (Ph+) ALL, the ASH guideline panel suggests reduced-intensity therapy (RIT) with a tyrosine kinase inhibitor (TKI) for remission induction over intensive chemotherapy (IC) with a TKI.

This is a conditional recommendation based on very low certainty in the evidence of effects. Philadelphia chromosome-positive ALL is a subtype of ALL in which leukemia cells have a specific genetic abnormality called the Philadelphia chromosome. This abnormality produces a protein that drives the growth of leukemia cells.

Tyrosine kinase inhibitors are drugs that block the activity of this abnormal protein. Examples of TKIs include imatinib, dasatinib, and ponatinib. Reduced-intensity therapy uses lower doses of chemotherapy than intensive chemotherapy.

This treatment should be followed by postremission therapy. Options include intensive chemotherapy plus a TKI and/or immunotherapy plus a TKI. Either of these approaches may be consolidated by allogeneic stem cell transplantation in first complete remission.

All patients with Ph+ ALL must receive central nervous system prophylaxis with concurrent intrathecal chemotherapy. Intrathecal chemotherapy is given directly into the cerebrospinal fluid that surrounds the brain and spinal cord.

The panel recognizes that postremission therapies, including allo-HSCT, are evolving. This evolution is driven by emerging data surrounding next-generation TKIs and novel or targeted immunotherapies.

This recommendation may not be as applicable to the youngest adolescents in the AYA subgroup. In these younger patients, pediatric-inspired regimens containing asparaginase would typically be applied. The panel appreciates that studies of pediatric-inspired backbones were not captured within the available data set.

Central Nervous System Prophylaxis

Recommendation 13: For AYAs with ALL receiving frontline therapy, the ASH guideline panel suggests the use of either intrathecal (IT) methotrexate or triple intrathecal therapy (TIT) for central nervous system (CNS) prophylaxis.

This is a conditional recommendation for either the intervention or comparison based on very low certainty in the evidence of effects. Central nervous system prophylaxis refers to treatment given to prevent leukemia cells from spreading to the brain and spinal cord.

Intrathecal methotrexate involves injecting the chemotherapy drug methotrexate directly into the cerebrospinal fluid. Triple intrathecal therapy combines three drugs: methotrexate, cytarabine, and hydrocortisone.

Hydrocortisone can be used in conjunction with intrathecal methotrexate for prevention of chemical arachnoiditis. Chemical arachnoiditis is inflammation of the membranes surrounding the brain and spinal cord that can occur as a side effect of intrathecal chemotherapy.

Cranial Radiation for CNS Prophylaxis

Recommendation 14: For AYAs with ALL receiving frontline therapy, the ASH guideline panel suggests against the routine use of cranial radiation for CNS prophylaxis for patients treated on a pediatric-inspired backbone containing asparaginase.

This is a conditional recommendation against the intervention based on very low certainty in the evidence of effects. Cranial radiation involves directing radiation therapy at the brain to prevent leukemia cells from growing there.

While cranial radiation can be effective at preventing CNS relapse, it also carries risks of long-term side effects. These can include cognitive problems, hormonal imbalances, and secondary cancers.

The panel notes there is uncertainty with respect to the use of cranial radiation for CNS prophylaxis for AYA individuals with T-ALL who are unable to receive nelarabine. For these patients, the risks and benefits of cranial radiation may be different.

Approach for Minimal Residual Disease

Recommendation 15: For patients with ALL with persistent MRD after at least 3 months of frontline therapy (induction plus a minimum of 1 block of postremission therapy), the ASH guideline panel recommends a change in approach to treatment.

This is a strong recommendation for the intervention based on very low certainty in the evidence of effects. Persistent MRD means that leukemia cells are still detectable in the bone marrow despite treatment.

The change in therapy could include several approaches including immunotherapy or allogeneic stem cell transplantation. Immunotherapy uses treatments that help the immune system fight cancer. Examples include blinatumomab and inotuzumab ozogamicin.

The optimal timing, choice of intervention or interventions, order, or combination of these approaches has not been defined. This means doctors must use their clinical judgment to determine the best approach for each individual patient.

This recommendation is addressed in Recommendation 9, which discusses the addition of blinatumomab for patients with B-ALL.

Good Practice Statements: Holistic Care for Young Adults

The guidelines include several good practice statements that address the comprehensive care needs of AYA patients with ALL. These statements recognize that treating the cancer is only part of providing optimal care.

Developmental needs: Given the unique challenges of cancer in adolescence and young adulthood, it is good practice for AYAs with ALL to have their developmental needs evaluated. The required developmental and contextual supports unique to AYAs should be considered. Whenever possible, treatment should be delivered with these considerations in mind, providing scheduling flexibility when not otherwise contraindicated.

Psychological support: Given the risk and prevalence of psychological comorbidities and adverse psychosocial outcomes during the cancer experience of AYAs with ALL, it is good practice to routinely screen for depression, anxiety, and other psychological comorbidities. Multidisciplinary psychosocial support should be implemented.

Social support: Given the unique social needs of AYAs with ALL, it is good practice to assess and evaluate each patient's existing social supports. Patients should be encouraged to connect with supportive communities when possible. This should be done through organized care coordination and resource navigation from a multidisciplinary team experienced in working with AYAs.

Financial support: Given the financial toxicity experienced by AYAs with ALL, it is good practice to provide financial counseling, resource navigation, and concrete resources. This can be provided through institutional means and/or in collaboration with larger regional or national organizations. Financial toxicity refers to the financial burden and distress caused by cancer treatment costs.

Sexual health: Given the importance of sexual health and sexuality for AYAs with ALL, along with the dynamic changes experienced in these areas over time, it is good practice to discuss sexual health, sexual orientation, sexual preferences, and gender identity of each individual patient. These discussions should begin from the onset of diagnosis, continue throughout the course of treatment, and extend into survivorship.

Fertility care: Given the importance of fertility and how it is affected by cancer and its therapy, it is good practice to provide AYAs with ALL access to comprehensive fertility care and consultation. This should involve the oncology provider, fertility specialist, and fertility counselors before the initiation of therapy whenever possible. Continued involvement and care from this multidisciplinary team should extend throughout therapy and into survivorship.

Clinical trial participation: Given that AYAs are underrepresented in cancer clinical trials, and improvement in survival over time has lagged in underrepresented populations of AYAs, it is good practice to offer AYAs treatment in appropriate clinical trials.

What These Guidelines Mean for Patients

These guidelines represent a significant step forward in standardizing care for adolescents and young adults with ALL. For patients and families, several key messages emerge.

First, pediatric-inspired regimens containing asparaginase are now strongly recommended as frontline therapy. This means patients should discuss with their care team whether they are receiving this type of treatment.

Second, allogeneic stem cell transplantation is not routinely recommended in first remission. However, certain high-risk patients may benefit from this approach. Patients should discuss their individual risk factors with their care team.

Third, targeted agents are increasingly supported in frontline therapy. This includes rituximab for CD20-positive B-ALL and blinatumomab for B-ALL. These treatments offer additional options for improving outcomes.

Fourth, the guidelines emphasize comprehensive supportive care. This includes managing asparaginase side effects, preventing blood clots, and providing psychosocial, financial, fertility, and sexual health support.

Fifth, monitoring for minimal residual disease is important. Patients with persistent MRD after at least 3 months of treatment should have their treatment approach changed.

Limitations of the Evidence

Many recommendations in these guidelines are based on very low certainty in the evidence of effects. This reflects the challenges of conducting research in a relatively rare cancer population.

Several recommendations are conditional rather than strong. This means that different choices will be appropriate for different patients, and clinicians must help each patient arrive at a management decision consistent with that patient's values and preferences.

For several treatment questions, the panel determined that the evidence is insufficient to issue a recommendation. These include:

• Routine VTE prophylaxis with low molecular weight heparin or direct oral anticoagulants
• Routine antithrombin replacement
• Resuming asparaginase after non-hypersensitivity toxicity
• Addition of inotuzumab ozogamicin for B-ALL
• Addition of nelarabine for T-ALL with all planned asparaginase doses
• Addition of bortezomib for T-LBL/LLy

The panel also recognizes uncertainty in several areas. These include the optimal asparaginase activity levels, the timing and duration of VTE prophylaxis, and the optimal approach for patients with persistent MRD.

The guidelines note that evidence in several areas is evolving. Recommendations may change as new data become available, particularly regarding targeted agents and postremission therapies for Philadelphia chromosome-positive ALL.

Actionable Recommendations for Patients and Families

Based on these guidelines, patients and families can take several steps to ensure optimal care:

1. Discuss your treatment regimen: Ask your care team whether you are receiving a pediatric-inspired regimen containing asparaginase. This is the strongly recommended frontline approach.
2. Understand your risk factors: Discuss with your care team whether you have any high-risk features that might affect treatment decisions, including MRD status, induction response, and biologic subtype.
3. Ask about targeted therapies: If you have B-ALL, ask whether rituximab or blinatumomab might be appropriate for your treatment.
4. Monitor for side effects: Report any symptoms of allergic reactions, blood clots, or other side effects to your care team promptly.
5. Request comprehensive support: Ask about psychosocial support, financial counseling, fertility preservation, and sexual health discussions as part of your care.
6. Consider clinical trials: Ask whether any clinical trials are available that might be appropriate for your situation.
7. Stay informed about MRD: Ask about your MRD status and how it is being monitored throughout your treatment.

These guidelines provide a framework for care, but individual treatment decisions should always be made in consultation with your health care team. Your values, preferences, and individual circumstances should guide these decisions.

Frequently Asked Questions

What is the recommended initial treatment for adolescents and young adults with acute lymphoblastic leukemia?

For adolescents and young adults with B-cell or T-cell acute lymphoblastic leukemia or T-cell lymphoblastic lymphoma receiving frontline therapy, guidelines strongly recommend pediatric-inspired regimens containing asparaginase. This recommendation is based on moderate certainty in the evidence. These regimens were originally developed for children and then adapted for adolescents and young adults. They require significant supportive care and close follow-up, meaning more frequent clinic visits and monitoring for side effects.

Is a stem cell transplant routinely recommended during first remission for adolescents and young adults with ALL?

No. Guidelines suggest against routinely proceeding with allogeneic hematopoietic stem cell transplantation as consolidation for adolescents and young adults with ALL in first complete remission. This is a conditional recommendation based on very low certainty in the evidence. However, certain high-risk subgroups may benefit, including patients with persistent minimal residual disease, induction failure, or high-risk biologic subsets. Discuss your individual risk factors with your care team.

What should I know about asparaginase side effects and managing them?

Asparaginase can cause serious side effects including allergic reactions, blood clotting problems, and pancreatic inflammation. Guidelines strongly recommend premedication with at minimum intravenous steroids, and possibly antihistamines or acetaminophen, before asparaginase to prevent hypersensitivity reactions. If an allergic reaction occurs with pegylated asparaginase, guidelines strongly recommend switching to an Erwinia-based asparaginase formulation rather than stopping asparaginase therapy. Therapeutic drug monitoring may be used to ensure adequate asparagine depletion.

What does it mean if I have persistent minimal residual disease after treatment?

Persistent minimal residual disease means leukemia cells are still detectable in the bone marrow after at least three months of frontline therapy, including induction plus at least one block of postremission therapy. Guidelines strongly recommend changing the treatment approach in this situation. Options may include immunotherapy such as blinatumomab or inotuzumab ozogamicin, or allogeneic stem cell transplantation. The optimal timing, choice, order, or combination of these approaches has not been defined, so doctors use clinical judgment.

Are targeted therapies like rituximab or blinatumomab recommended for B-ALL?

For adolescents and young adults with CD20-positive B-ALL receiving frontline therapy, guidelines suggest adding rituximab to standard chemotherapy. For those with B-ALL who achieve morphologic remission, guidelines suggest adding blinatumomab regardless of minimal residual disease status. Both are conditional recommendations based on very low certainty in the evidence. Uncertainties remain about optimal dosing, timing, and which patients benefit most. Discuss with your care team whether these therapies might be appropriate for you.

What supportive care should be part of my treatment?

Guidelines include good practice statements emphasizing holistic care. This includes evaluating developmental needs, routinely screening for depression and anxiety, assessing social supports, providing financial counseling and resource navigation, discussing sexual health and gender identity from diagnosis through survivorship, and offering comprehensive fertility care before therapy when possible. Also, guidelines recommend offering treatment in appropriate clinical trials because adolescents and young adults are underrepresented in cancer research.

What is central nervous system prophylaxis and how is it given?

Central nervous system prophylaxis is treatment to prevent leukemia cells from spreading to the brain and spinal cord. Guidelines suggest using either intrathecal methotrexate or triple intrathecal therapy, which combines methotrexate, cytarabine, and hydrocortisone. This is a conditional recommendation based on very low certainty in the evidence. Guidelines also suggest against routine cranial radiation for central nervous system prophylaxis in patients treated on a pediatric-inspired backbone containing asparaginase, due to risks of long-term side effects.

I'm an adolescent or young adult just diagnosed with acute lymphoblastic leukemia — when should I seek a second opinion about my treatment plan?

A second opinion is worth considering at diagnosis, before frontline therapy begins, because the recommended approach differs from what many adult settings use. Guidelines strongly recommend pediatric-inspired regimens containing asparaginase for B-ALL, T-ALL and T-LBL/LLy, and suggest against routine allogeneic stem cell transplant in first remission except for high-risk patients such as those with persistent minimal residual disease or induction failure. Reviewing your subtype, MRD status and risk factors with another specialist can clarify whether targeted agents like rituximab or blinatumomab fit your situation. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original Article Title: American Society of Hematology 2026 guidelines for frontline management of acute lymphoblastic leukemia in adolescents and young adults.

Journal: Blood advances

License: CC BY-NC-ND (open access)

Authors: DuVall AS, McNeer J, Cheung MC, Adrianzen-Herrera DA, Advani A, Aljurf M, Audino A, Benitez L, Deeter A, Dworkin E, Hiltbrand O, Isenalumhe L, Li L, Miller-Chism C, Mozessohn L, Ng AP, Pu JJ, Shafer D, Madueno FV, Viny A, Wadhwa A, Yang J, Zarnegar-Lumley S, Mai HJ, Kanaan G, Sereda Y, Saldanha IJ, Balk EM, Stock W, Wolfson JA.

Publication: Blood Advances, July 14, 2026, Volume 10, Number 13

DOI: https://doi.org/10.1182/bloodadvances.2021006469

Publisher: American Society of Hematology, published by Elsevier Inc.

Note: This patient-friendly article is based on peer-reviewed research. The original guidelines were developed by the American Society of Hematology and are intended to support patients, clinicians, and other health care professionals in their decisions about the frontline management of acute lymphoblastic leukemia in adolescents and young adults.