Table of Contents
- Key Points
- Background: Why This Guideline Matters
- How the Guidelines Were Developed
- Understanding the Recommendations
- Key Recommendations: Reinduction Therapy for B-ALL
- CAR T-Cell Therapy: What the Panel Could and Could Not Recommend
- Consolidation with Allogeneic Stem Cell Transplant
- Preparing for Transplant: Conditioning Regimens
- Central Nervous System Relapse
- T-Cell ALL: A Different Disease, A Different Approach
- Good Practice Statements: Caring for the Whole Person
- What the Panel Valued Most
- Limitations of the Evidence
- What This Means for Patients and Families
- Frequently Asked Questions
- Source Information
Key Points
- The 2026 ASH guidelines provide the first comprehensive, evidence-based recommendations for treating relapsed or refractory ALL in adolescents and young adults ages 15 to 39.
- For relapsed or refractory B-ALL, the panel strongly recommends blinatumomab and inotuzumab over chemotherapy alone for reinduction, based on low certainty evidence.
- The panel could not recommend one immunotherapy over another because almost no head-to-head comparisons exist among blinatumomab, inotuzumab, and CAR T-cell therapy.
- For isolated CNS relapse, the panel strongly recommends intrathecal chemotherapy with systemic therapy and strongly recommends against CNS radiation alone.
- Good practice statements address fertility counseling, mental health screening, financial toxicity, sexual health, clinical trial participation, and early palliative care for AYAs.
Background: Why This Guideline Matters
Acute lymphoblastic leukemia (ALL) is a cancer of the blood and bone marrow that is challenging to treat, especially in adolescents and young adults. The National Cancer Institute defines AYAs with cancer as individuals diagnosed between the ages of 15 and 39 years.
This age group sits at the boundary between pediatric and adult oncology. That position creates unique problems. AYAs with relapsed or refractory ALL experience greater treatment resistance than younger children. They also have higher rates of treatment-related toxicity. And they face these challenges at a specific life stage with distinct priorities, such as education, career, relationships, and family planning.
Frontline treatment for ALL has improved significantly and reduces the risk of recurrence. However, relapse remains a critical concern with overall poor prognosis. This underscores the urgent need for effective interventions that treat relapse.
For relapsed ALL, the goal of achieving a second complete remission (CR2) has historically guided treatment strategies. A second remission often serves as a bridge to allogeneic hematopoietic stem cell transplant (allo-HSCT), a procedure that replaces a patient's diseased bone marrow with healthy donor stem cells.
Despite advances in treatment including immunotherapy, significant differences remain between pediatric and adult approaches to relapsed or refractory ALL. These differences potentially stem from variations in disease biology and treatment tolerance. The 2026 ASH guidelines aim to address these gaps with recommendations tailored specifically to the AYA population.
How the Guidelines Were Developed
The American Society of Hematology formed a multidisciplinary guideline panel to develop these recommendations. The panel included hematologists, AYA psychosocial care specialists, pharmacists, methodologists, and patient representatives. The panel made efforts to minimize bias from conflicts of interest.
An evidence review team at Brown University supported guideline development. This team performed 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. This process included GRADE Evidence-to-Decision frameworks. All recommendations were subject to public comment before finalization.
The guideline development process followed best practices recommended by the Institute of Medicine and the Guidelines International Network (GIN). The panel used the GIN-McMaster Guideline Development Checklist to guide its work. ASH funded the work under a paid agreement with Brown University School of Public Health.
Two panels worked in parallel on ALL in AYAs and collaborated on protocol development. The ASH Guideline Oversight Subcommittee provided project oversight for both panels. This subcommittee reported to the ASH Committee on Quality.
Understanding the Recommendations
The guidelines use specific language to communicate the strength of each recommendation. Understanding this language helps patients and families interpret what the panel intended.
Strong recommendations use the phrase "the guideline panel recommends." When the panel makes a strong recommendation, most individuals in that situation would want the recommended course of action. Only a small proportion would not. Clinicians should generally follow the recommended course of action, and formal decision aids are not likely needed.
Conditional recommendations use the phrase "the guideline panel suggests." When the panel makes a conditional recommendation, most individuals would want the suggested course of action, but many would not. Different choices will be appropriate for different patients. Clinicians must help each patient arrive at a management decision consistent with that patient's values and preferences. Decision aids may be useful in these situations.
Good practice statements endorse interventions or practices that the panel agreed have unequivocal net benefit. These practices may not be widely recognized or used. Good practice statements are not based on a systematic review of available evidence. Nevertheless, they may be interpreted as strong recommendations.
Research-only recommendations are actionable guidelines that confine the use of an intervention within a specific population strictly to a research setting. The panel issues these when existing evidence is insufficient for a formal recommendation but the intervention has potential to significantly reduce uncertainty.
The guidelines also use a certainty rating system. This system ranges from very low certainty (one filled circle out of four) to high certainty (four filled circles out of four). Many recommendations in these guidelines are based on low or very low certainty evidence, reflecting the limited research available specifically for the AYA population.
Key Recommendations: Reinduction Therapy for B-ALL
Reinduction therapy aims to bring the leukemia back into remission. The panel made two strong recommendations for reinduction in B-cell ALL (B-ALL), the most common form of ALL.
Recommendation 1: For AYAs with relapsed or refractory B-ALL, the ASH guideline panel recommends the use of blinatumomab over chemotherapy alone. This is a strong recommendation based on low certainty in the evidence of effects.
Blinatumomab is a type of immunotherapy called a bispecific T-cell engager. It works by helping the patient's own immune system recognize and attack leukemia cells.
The panel highlighted one important consideration. Some patients with high leukemia cell counts (high blast counts) at relapse may need debulking before proceeding with blinatumomab. Debulking means reducing the amount of cancer in the body before giving the immunotherapy.
Recommendation 2: For AYAs with relapsed or refractory B-ALL, the ASH guideline panel recommends the use of inotuzumab over chemotherapy. This is also a strong recommendation based on low certainty in the evidence of effects.
Inotuzumab ozogamicin (InO) is an antibody-drug conjugate. It delivers a chemotherapy payload directly to leukemia cells that carry a specific marker called CD22.
The panel highlighted the need to consider the risk of veno-occlusive disease (VOD) in individuals who are intended to proceed with allogeneic stem cell transplant following inotuzumab ozogamicin. VOD is a serious liver condition that can occur after stem cell transplant. Patients and their care teams should discuss this risk when planning treatment sequences.
CAR T-Cell Therapy: What the Panel Could and Could Not Recommend
Chimeric antigen receptor (CAR) T-cell therapy is a treatment that modifies a patient's own immune cells to attack leukemia. The panel recognized the notable utility of CAR T-cell therapy following relapse based on existing single-arm studies. However, the panel could not make a formal recommendation comparing CAR T-cell therapy to chemotherapy or other immune-based therapies.
The reason is that minimal comparative data exist to review. There are almost no head-to-head comparisons of the three main immunotherapy options: blinatumomab, inotuzumab, and CAR T-cell therapy. The best sequence for using these therapies is not yet understood.
Therefore, the ASH guideline panel was unable to recommend one agent over another. The choice should be made based on individual patient assessment, burden of disease, and candidacy for future consolidative therapy including allogeneic stem cell transplant.
This means that patients and their doctors must make these decisions together, weighing the specific circumstances of each case. There is no single "right" answer that applies to everyone.
Consolidation with Allogeneic Stem Cell Transplant
After achieving remission, consolidation therapy aims to keep the leukemia from returning. Allogeneic hematopoietic stem cell transplant (allo-HSCT) is one consolidation option. This procedure uses stem cells from a healthy donor.
Recommendation 3: For AYAs who have not previously had a stem cell transplant and who achieve a second or greater remission (CR2) with FDA-approved autologous CD19 CAR T-cell products, the ASH guideline panel suggests further consolidation with allogeneic stem cell transplant. This is a conditional recommendation based on very low certainty in the evidence of effects.
The FDA-approved CAR T-cell products referenced are tisagenlecleucel and brexucabtagene autoleucel. These treatments use the patient's own modified T cells (autologous means from the same person).
The panel recognized emerging evidence that could help identify individuals and clinical scenarios in which CAR T-cell therapy alone is sufficient. The panel also recognized scenarios in which the risks of transplant might outweigh the benefit. Individualized patient assessment and shared decision-making are warranted in these situations.
Recommendation 4: For AYAs with relapsed B-ALL who achieve a second or greater remission, the ASH guideline panel suggests allogeneic stem cell transplant over chemotherapy alone as definitive consolidation treatment. This is a conditional recommendation based on very low certainty in the evidence of effects.
The panel provided several important remarks for this recommendation:
- AYAs with primary refractory disease in whom remission is achieved should proceed with allogeneic stem cell transplant. Primary refractory means the disease never went into remission with initial treatment.
- The recommendation for allogeneic stem cell transplant must be balanced with systematic assessments of patient suitability for transplant. These assessments include performance status, organ function, and other health conditions (comorbidities).
- The panel recognizes that pediatric data indicate some younger AYAs in second remission with lower risk disease may be considered for chemotherapy and/or immunotherapy alone. Lower risk disease is defined by late relapse with low minimal residual disease (MRD) after reinduction therapy. MRD refers to small numbers of leukemia cells that remain in the body after treatment, below the level detectable by standard methods.
Preparing for Transplant: Conditioning Regimens
Before an allogeneic stem cell transplant, patients receive conditioning therapy. This treatment prepares the body to receive donor stem cells. Conditioning regimens may include chemotherapy alone or chemotherapy combined with total body irradiation (TBI), which is radiation directed at the entire body.
Recommendation 5: For AYAs with relapsed or refractory ALL proceeding with allogeneic stem cell transplant, the ASH guideline panel suggests myeloablative conditioning regimens that include total body irradiation rather than chemotherapy alone. This is a conditional recommendation based on very low certainty in the evidence of effects.
Myeloablative conditioning means the regimen uses higher doses of treatment to more completely eliminate diseased bone marrow before transplant. This approach is more intensive than reduced-intensity conditioning.
Central Nervous System Relapse
Sometimes ALL returns in the central nervous system (CNS), which includes the brain and spinal cord. This is called an isolated CNS relapse when the leukemia is found only in the CNS and not in the bone marrow or other locations.
Recommendation 6: For AYAs with isolated CNS relapse of ALL, the ASH guideline panel recommends that patients receive CNS-directed therapy (intrathecal chemotherapy) in the context of systemic therapy. This is a strong recommendation based on very low certainty in the evidence of effects.
Intrathecal chemotherapy means chemotherapy delivered directly into the fluid surrounding the brain and spinal cord. Systemic therapy means treatment that reaches the whole body, such as intravenous chemotherapy.
Recommendation 7: For AYAs with isolated CNS relapse of ALL, the ASH guideline panel recommends against patients receiving CNS radiation alone without systemic chemotherapy with intrathecal chemotherapy. This is a strong recommendation against the intervention based on very low certainty in the evidence of effects.
This means radiation by itself, without chemotherapy that reaches the whole body and chemotherapy delivered directly to the CNS, is not recommended.
The panel noted insufficient data to support a recommendation regarding the additional benefit of radiation when combined with other CNS-directed therapy.
The panel also recognized promising emerging data for the use of CAR T-cell therapy in managing isolated CNS relapse. However, the data are insufficient to support a recommendation at this time.
T-Cell ALL: A Different Disease, A Different Approach
T-cell acute lymphoblastic leukemia (T-ALL) is a less common form of ALL that affects T cells rather than B cells. Treatment approaches differ from those for B-ALL.
Recommendation 8: For AYAs with relapsed or refractory T-cell acute lymphoblastic leukemia, the ASH guideline panel suggests the use of a nelarabine-based regimen. This is a conditional recommendation based on very low certainty in the evidence of effects.
Nelarabine is a chemotherapy drug specifically active against T-cell leukemia. The panel noted that many AYAs are receiving nelarabine as part of their frontline (initial) treatment. However, no data suggest that AYAs who have received nelarabine previously should be precluded from receiving it again.
Research-only recommendation: There is limited available evidence for novel therapies, including CAR T-cell therapy, in relapsed or refractory T-ALL. The ASH guideline panel is currently unable to issue a formal recommendation regarding these treatment approaches. This is despite recognizing that early phase data appear promising.
The panel thus issues a research-only recommendation. If available and feasible, individuals with relapsed or refractory T-ALL should be offered participation in clinical trials of novel therapies, including CAR T-cell therapy.
Good Practice Statements: Caring for the Whole Person
The guidelines include numerous good practice statements that address the broader needs of AYAs with ALL. These statements recognize that treating the cancer is only part of comprehensive care.
Minimal residual disease testing: Measurement of disease response using MRD is considered standard of care in AYA ALL. MRD testing provides prognostic value and, in some cases, helps determine treatment intensity.
Developmental needs: Given the unique challenges of cancer in AYA, it is good practice for AYAs with ALL to have their developmental needs evaluated. Their preferences and goals for treatment should be assessed within their unique developmental context. Whenever possible, treatment should be delivered with consideration of their developmental stage, providing scheduling flexibility when not otherwise contraindicated.
Mental health: Given the risk and prevalence of psychological comorbidities and adverse psychosocial outcomes during the cancer experience, it is good practice to routinely screen for depression, anxiety, and other psychological conditions. Multidisciplinary psychosocial support should be implemented.
Social support: Given the unique social needs of AYAs with ALL, it is good practice to assess each patient's existing social supports. Connection with supportive communities should be encouraged where possible. This should occur through organized care coordination and resource navigation from a multidisciplinary team experienced in working with AYAs.
Financial toxicity: Given the financial toxicity experienced by AYAs with ALL, it is good practice to provide financial counseling, resource navigation, and concrete resources. This may occur through institutional means and/or in collaboration with larger regional or national organizations.
Sexual health: Given the importance of sexual health and sexuality for AYAs with ALL, along with dynamic changes experienced in these areas over time, it is good practice to discuss sexual health, sexual orientation, sexual preferences, and gender identity. These discussions should begin at the onset of diagnosis, continue throughout treatment, and extend into survivorship.
Fertility: Given the importance of fertility and how cancer and its therapy affect it, it is good practice to provide fertility counseling to AYAs with ALL. This should occur at diagnosis, before initiation of therapy whenever possible. Counseling should involve a reproductive endocrinologist, fertility specialist, and fertility counselors. 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 an appropriate clinical trial.
Palliative care: It is good practice to introduce interdisciplinary palliative care teams as early as possible in treatment. Interdisciplinary and/or primary palliative care (delivered by the treating oncology team) should remain a focus of care throughout the care continuum, regardless of disease status.
Goals of care: It is good practice to discuss goals of care and end-of-life concepts earlier in treatment, before disease- or symptom-related crises arise. These discussions should be ongoing, tailored to the AYA's developmental and cognitive level, and centered on the wishes of the AYA. They should involve families and/or caregivers to the extent desired by the AYA. End-of-life care goals should be readdressed at key transition points during care, such as relapse.
Access to specialized care: Considering differential outcomes for AYAs by location of care, it is good practice to ensure AYAs with ALL have access to specialized care. This care should be provided by professionals and institutions well versed in AYA ALL where feasible.
What the Panel Valued Most
The panel's recommendations place a relatively higher value on overall survival (OS) than on other outcomes. The panel placed a relatively lower value on minimizing toxicities, regardless of their long-term impact on quality of life.
This value judgment reflects the panel's prioritization of survival, including that of patient representatives. This prioritization informed the development of recommendations across all sections.
This means the panel prioritized treatments that offer the best chance of survival, even when those treatments may cause more side effects or affect quality of life. Patients should discuss with their care teams how these values align with their own priorities.
Limitations of the Evidence
Many recommendations in these guidelines are based on low or very low certainty in the evidence of effects. This reflects the limited research available specifically for the AYA population.
AYAs are underrepresented in cancer clinical trials. This underrepresentation has contributed to lagging survival improvements in some AYA populations. The evidence base for treating relapsed or refractory ALL in AYAs often must be extrapolated from pediatric or older adult studies.
Extrapolating benefits and harms from other populations to AYAs introduces uncertainty. The panel made efforts to leverage the best available data to tailor specific recommendations for this population.
The panel identified several areas where future research is needed:
- Head-to-head comparisons of blinatumomab, inotuzumab, and CAR T-cell therapy
- The best sequence for using these therapies
- Identifying which patients can be treated with CAR T-cell therapy alone without transplant
- Identifying which patients face risks from transplant that outweigh benefits
- Novel therapies for T-ALL, including CAR T-cell therapy
- CAR T-cell therapy for isolated CNS relapse
- Quality of life outcomes with special attention to the unique AYA population
Future research should evaluate these approaches with special attention to the unique AYA population. Studies should also evaluate quality of life outcomes.
What This Means for Patients and Families
These guidelines provide a framework for making treatment decisions, but they are not a one-size-fits-all prescription. The panel emphasized shared decision-making throughout.
For patients with relapsed or refractory B-ALL, the guidelines strongly favor immunotherapy approaches (blinatumomab and inotuzumab) over chemotherapy alone for reinduction. This represents a significant shift toward more targeted treatments.
For patients who achieve remission, allogeneic stem cell transplant remains an important consolidation option. However, the guidelines recognize that some patients, particularly younger AYAs with lower risk disease, may be considered for other approaches.
The guidelines also emphasize that treating the whole person matters. Mental health support, fertility counseling, financial navigation, and attention to developmental needs are not optional extras. They are part of good cancer care for AYAs.
Patients and families should feel empowered to ask their care teams about:
- Whether immunotherapy approaches are appropriate for their specific situation
- Whether they are candidates for allogeneic stem cell transplant
- What clinical trials might be available
- How their mental health, fertility, and financial needs will be addressed
- What their goals of care are and how treatment aligns with those goals
The panel's decision to prioritize survival over minimizing toxicity reflects the seriousness of relapsed or refractory ALL. However, individual patients may weigh these factors differently. Open communication with care teams about personal values and priorities is essential.
Frequently Asked Questions
What are the 2026 ASH guidelines for relapsed or refractory ALL in adolescents and young adults?
The American Society of Hematology released guidelines in 2026 for treating adolescents and young adults, ages 15 to 39, whose acute lymphoblastic leukemia has returned or stopped responding. The expert panel made eight formal recommendations and one research-only recommendation. They cover reinduction and consolidation therapy, allogeneic stem cell transplant, central nervous system relapse, T-cell ALL, and quality-of-life issues including fertility, mental health, and financial support.
What does a strong recommendation mean in these guidelines?
A strong recommendation uses the phrase 'the guideline panel recommends.' It means most people in that situation would want the recommended course of action, and only a small proportion would not. Clinicians should generally follow it, and formal decision aids are not likely needed. A conditional recommendation uses 'the guideline panel suggests,' meaning choices will differ between patients and decision aids may help.
What reinduction treatment does the panel recommend for relapsed or refractory B-ALL?
For adolescents and young adults with relapsed or refractory B-cell ALL, the panel strongly recommends blinatumomab over chemotherapy alone, and inotuzumab over chemotherapy. Both are based on low certainty evidence. Blinatumomab is a bispecific T-cell engager that helps the immune system attack leukemia cells. Inotuzumab is an antibody-drug conjugate delivering chemotherapy to cells carrying the CD22 marker. Patients with high blast counts may need debulking before blinatumomab.
What is the risk of veno-occlusive disease with inotuzumab before transplant?
The panel highlighted the need to consider the risk of veno-occlusive disease, a serious liver condition that can occur after stem cell transplant, in people intended to proceed with allogeneic stem cell transplant following inotuzumab ozogamicin. Patients and their care teams should discuss this risk when planning treatment sequences. This was noted alongside the strong recommendation for inotuzumab over chemotherapy for relapsed or refractory B-ALL.
Why couldn't the panel recommend CAR T-cell therapy over other options?
The panel recognized the notable utility of CAR T-cell therapy after relapse based on existing single-arm studies. However, it could not make a formal recommendation comparing CAR T-cell therapy to chemotherapy or other immune-based therapies because minimal comparative data exist. There are almost no head-to-head comparisons of blinatumomab, inotuzumab, and CAR T-cell therapy, and the most appropriate sequence is not yet understood. Choices should be made based on individual assessment.
What does the panel recommend for allogeneic stem cell transplant after remission?
For adolescents and young adults with relapsed B-ALL who achieve a second or greater remission, the panel suggests allogeneic stem cell transplant over chemotherapy alone as definitive consolidation. This is a conditional recommendation based on very low certainty evidence. For those who achieve remission with FDA-approved autologous CD19 CAR T-cell products and have not had a transplant, the panel suggests further consolidation with allogeneic stem cell transplant. Individualized assessment and shared decision-making are warranted.
What does the panel recommend for isolated central nervous system relapse?
For adolescents and young adults with isolated central nervous system relapse of ALL, the panel strongly recommends CNS-directed therapy, meaning intrathecal chemotherapy, in the context of systemic therapy. It also strongly recommends against CNS radiation alone without systemic chemotherapy with intrathecal chemotherapy. The panel noted insufficient data on the additional benefit of radiation when combined with other CNS-directed therapy, and insufficient data to recommend CAR T-cell therapy for this situation.
My ALL has relapsed and my doctor recommends blinatumomab or inotuzumab instead of chemotherapy — when should I get a second opinion?
The 2026 ASH guidelines strongly recommend blinatumomab or inotuzumab over chemotherapy alone for relapsed or refractory B-ALL in adolescents and young adults, but the choice between these immunotherapies and CAR T-cell therapy rests on individual assessment, disease burden, and transplant candidacy, since no head-to-head comparisons exist. A second opinion can help confirm which approach fits your situation, whether transplant consolidation is appropriate, and how risks such as veno-occlusive disease are weighed. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: American Society of Hematology 2026 guidelines for management of relapsed/refractory acute lymphoblastic leukemia in adolescents and young adults.
Authors: O'Dwyer K, Winestone LE, Cheung MC, Benitez L, Buldini B, Cole PD, Damlaj M, Dholaria B, Dias AL, Dils A, Fritsch M, Greer J, Hayes-Lattin B, Henry M, Jaffe A, Jamy O, Kebriaei P, Mehrtens I, Shah NN, Wilde L, Young PA, Mai HJ, Kanaan G, Sereda Y, Saldanha IJ, Balk EM, Gupta S.
Publication: Blood Advances, 14 July 2026, Volume 10, Number 13, pages 4726-4729
DOI: https://doi.org/10.1182/bloodadvances.2021006479
Submitted: 6 October 2025; Accepted: 28 December 2025; Prepublished online: 11 February 2026; Final version published online: 30 June 2026
This patient-friendly article is based on peer-reviewed research.
