eBulletin Newsletter

NCCN Flash Updates: NCCN Guidelines Updated for Pediatric Acute Lymphoblastic Leukemia

NCCN has published updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®), the NCCN Drugs & Biologics Compendium (NCCN Compendium^®), the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™) for Pediatric Acute Lymphoblastic Leukemia. These NCCN Guidelines^® are currently available as Version 1.2025.

Link directly to the Updates section of the NCCN Guidelines: Pediatric Acute Lymphoblastic Leukemia

Global changes:

• References updated throughout the guideline.
• All instances of Ph modified to BCR::ABL1

PEDALL-1

• Classification
  • First bullet modified: Together, these studies allow determination of the World Health Organization (WHO) and International Consensus Criteria (ICC) ALL subtypes and genetic risk groups (ALL Subtypes [PEDALL-A] and Genetic Risk Groups for B-ALL [PEDALL-B])

PEDALL-1A

• Footnote b modified: B-ALL/LL subtypes include those not otherwise specified (NOS), with high hyperdiploidy, hypodiploidy, and intrachromosomal amplification of chromosome 21 (iAMP21), with commonly recurring genetic abnormalities: t(9;22)(q34.1;q11.2)[BCR::ABL1]; BCR::ABL1–like (Ph-like) B-ALL; t(v;11q23.3)[KMT2A rearrangement]; t(12;21)(p13.2;q22.1)[ETV6::RUNX1]; ETV6::RUNX1-like features, t(1;19)(q23;p13.3)[TCF3::PBX1]; t(5;14)(q31.1;q32.3)[IGH::IL3]; t(17;19)(q22;p13.3)[TCF3::HLF]; and t(17;18)(q22;q21.2)[TCF4::HLF] and with other defined genetic abnormalities that include rearrangements of DUX4, MEF2D, ZNF384, and NUTM1; IG::MYC fusion; and PAX5alt, and with PAX5 p.P80R, IKZF1 p.N159Y, and CDX2/UBTF. Of note, in cases of poor response to ALL therapy for ALL with IG::MYC rearrangement, therapy for mature B-cell lymphoma may be considered.
• Footnote e modified: Criteria for classification of mixed phenotype acute leukemia (MPAL) should be based on the WHO 2016 2022 and ICC 2022 criteria. Note that in ALL, myeloid-associated antigens such as CD13 and CD33 may be expressed, and the presence of these myeloid markers does not exclude the diagnosis of ALL, nor is it associated with adverse prognosis. ALL-directed therapy can be initiated for MPAL. Khoury JD, et al. Leukemia 2022;36:1703-1719; Arber DA, et al. Blood 2022;140:1200-1228; Alexander TB, et al. Nature 2018;562:373-379.
• Footnote f modified: For Burkitt leukemia/lymphoma; see the NCCN Guidelines for Pediatric Aggressive Mature B-Cell Lymphomas NCCN Guidelines for B-Cell Lymphomas.
• Footnote i modified: The following immunophenotypic findings are particularly notable: CD10 negativity correlates with KMT2A rearrangement (KMT2Ar); ETP T-ALL (ETP T-ALL typically lacks lacking expression of CD5, CD8, and CD1a and has expression of one or more myeloid/stem cell markers); CD20 positivity: definition not clear, most studies have used >20% of blasts expressing CD20; and CRLF2 overexpression as a surrogate for genomic alterations of the CRLF2 gene including CRLF2::P2RY8::CRLF2 and IGH::CRLF2 (Harvey RC, et al. Blood 2012;120:2529). Flow cytometric DNA ploidy analysis could be considered for rapid identification of hyperdiploid and hypodiploid B-ALL.
• Footnote k modified: The BCR::ABL1–like (Ph-like) phenotype is associated with recurrent gene fusions and mutations that activate tyrosine kinase pathways and includes gene fusions involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, or PDGFRB and mutations involving CRLF2, FLT3, IL7R, SH2B3, JAK1, JAK3, and JAK2 (in combination with CRLF2 gene fusions). Testing for these abnormalities at diagnosis may aid in risk stratification. Low-density array (LDA) (Harvey RC, et al. Blood 2013;122:21), NGS-based assays, FISH, and multiplex RT-PCR are used to detect a signature or cryptic rearrangements and mutations characteristic of BCR::ABL1–like ALL. The safety and efficacy of targeted agents in this population is an area of active research.

PEDALL-2

• Workup
  • 5th bullet modified: Pregnancy testing, fertility counseling, and preservation as indicated
  • 6th bullet added: Fertility counseling is recommended for all patients, with fertility preservation as clinically appropriate [see NCCN Guidelines for Adolescent and Young Adult (AYA) Oncology]
  • 7th bullet added: Psychosocial assessment is encouraged (for AYA, see NCCN Guidelines for AYA Oncology)
  • 8th bullet added: For AYA, counseling on cessation of smoking, drugs/illicit substances, vaping, and alcohol is encouraged (see NCCN Guidelines for Smoking Cessation)
  • Last bullet
    • 2nd sub bullet modified: For non-Down syndrome-related ALL the majority of patients do not have an identifiable leukemia predisposition syndrome. One important exception is low hypodiploid (32–39 chromosomes) ALL where pathologic germline TP53 variants mutations are common and testing should be considered.
    • 3rd sub bullet modified: Other pathologic germline variants mutations associated with ALL risk have been reported. A complete family history can help identify risk for a cancer predisposition syndrome, although de-novo variants mutations have been reported.
    • 4th sub bullet added: There are increasing data to suggest that ALL can present as a second malignancy.

PEDALL-2A

• Footnote m added: Fertility preservation is an option for certain patients. Options include sperm cryopreservation, oocyte cryopreservation, harvesting of ovarian or testicular tissue for cryopreservation, or embryo cryopreservation. Referral to a fertility preservation/reproductive health program should be considered for certain patients. Mulder RL, et al. Lancet Oncol 2021;22:e45-e56; Mulder RL, et al. Lancet Oncol 2021;22:e57-e67.
• Footnote p modified: Genes for pathologic germline variants are Germline mutations in genes often somatically mutated in ALL, particularly PAX5, ETV6, and IKZF1, and have been shown to confer predisposition to developing B-ALL. Pui CH, et al. Nat Rev Clin Oncol 2019;16:227-240.
• Footnote q added: Hunger SP, et al. J Clin Oncol 1992;10:156-163; Hijiya N, et al. Cancer 2009;115:23-35.

PEDALL-3

• Algorithm modified to include complete remission and less than complete remission.
• Footnote t modified: Standard risk criteria include are consistent with NCI: white blood cell (WBC) count <50,000/mm³ and ≥1 y to <10 y, but there are other clinical features that may impact initial risk stratification. For further details, see the Risk Stratification Definitions (PEDALL-F).
• Footnote u modified: High-risk criteria include are consistent with NCI: WBC count ≥50,000/mm³ and <1 y or ≥10 y, but there are other clinical features that may impact initial risk stratification. For further details, see the Risk Stratification Definitions (PEDALL-F).

PEDALL-A

• New section added: ALL Subtypes

PEDALL-B

• Genetic Risk Groups For B-ALL
  • Intermediate risk features modified: MEF2Dr, ZNF384r, PAX5alt, PAX5 P80R, ETV6::RUNX1-like, t(1;19): TCF3::PBX1
• Footnote c modified: Alternatively defined as DNA index less than protocol-defined threshold or other clear evidence of hypodiploid clone: near-haploid (24–31 chromosomes); low-hypodiploid (32–39 chromosomes); or high-hypodiploid (40–43 chromosomes). Low hypodiploid ALL is also often associated with TP53 loss-of-function somatic mutations in which half are observed to be germline pathogenic variants associated with and Li-Fraumeni syndrome. Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 2013;45:242-252.
• Footnote f modified: IKZF1 deletions with deletions in CDKN2A, CDKN2B (homozygous), PAX5, or PAR1 region in the absence of ERG deletion, which are called IKZF1plus, as well as those with concomitant 22q11.22 deletions are especially associated with worse outcomes. However, DUX4 rearrangements with IKZF1 alterations do not confer poor prognosis. Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 2009;360:470-480; Stanulla M, Dagdan E, Zaliova M, et al. IKZF1plus defines a new minimal residual disease-dependent very-poor prognostic profile in pediatric B-cell precursor acute lymphoblastic leukemia. J Clin Oncol 2018;36:1240-1249; Mangum DS, Meyer JA, Mason CC, et al. Association of combined focal 22q11.22 deletion and IKZF1 alterations with outcomes in childhood acute lymphoblastic leukemia. JAMA Oncol 2021;7:1521-1528.

PEDALL-C (1 of 14)

• Infection Control
  • 3rd bullet, 3rd sub bullet modified: Consider antifungal prophylaxis during induction, especially in patients receiving anthracyclines. Azoles have potential interactions with vincristine and should be used with caution. Consider micafungin or other echinocandin antifungal drugs during induction and potentially during other high-intensity phases. Prophylaxis with liposomal amphotericin can be considered is also allowed.
  • 5th bullet
    • 1st sub bullet modified: During induction, all patients with fever (as defined by Infectious Diseases Society of America [IDSA] or institutional standards) should be evaluated by a medical provider and treated immediately with broad-spectrum antibiotics, regardless of absolute neutrophil count (ANC). Following completion of induction, antibiotics may not be indicated for fever based on clinical status.
    • 5th sub bullet modified: For patients with signs of Antibiotics should be administered as soon as possible and within one hour of presentation with fever, neutropenia, or sepsis, antibiotics should be administered as soon as possible. Recommend stress dose steroids for patients with sepsis.

PEDALL-C (2 of 14)

• 10th sub bullet
  • 1st sub sub bullet modified: In a hemodynamically stable patient, monotherapy with a broad-spectrum antibiotic an anti-pseudomonal agent with activity against gram-positive and gram-negative bacteria (including Pseudomonas) is recommended.
  • 7th sub sub bullet modified: If blood cultures at 24–48 hours identify Gram-positive bacteria, consider obtaining obtain one set of repeat blood cultures and starting start vancomycin (or linezolid in a patient with a history of vancomycin-resistant enterococci [VRE]) pending results of repeat cultures and final identification and susceptibilities of the Gram-positive bacteria. If cultures at 48 hours do not reveal a Gram-positive infection and vancomycin was started, it can be discontinued at 48 hours.
• 11th sub bullet: Filgrastim (granulocyte colony-stimulating factor [G-CSF]), pegfilgrastim, and sargramostim (granulocyte-macrophage colony-stimulating factor [GM-CSF]), and granulocyte transfusions are not generally recommended but may be used at the discretion of the health care provider in situations of prolonged neutropenia or serious/life-threatening infections with in the context of neutropenia. Similarly, granulocyte transfusions are not generally recommended but may be used at the discretion of the health care provider in situations of serious/life-threatening infection in the context of neutropenia.

PEDALL-C (3 of 14)

• 1st bullet, 1st sub bullet modified: Additional diagnostic investigation, such as imaging radiographic evaluation of lungs, abdomen, and sinuses if symptomatic, should be considered and empirical antifungal therapy should be started for patients with neutropenia and prolonged (≥4–7 days) fever despite empirical antibiotics and who are expected to remain neutropenic, or who have new symptoms (eg, cough, facial pain, swelling).
• 2nd bullet modified: Consider vaccination with inactivated vaccines and live vaccines (Patients should be vaccinated for varicella, measles, mumps, and rubella) 3 months after chemotherapy following the CDC schedule for immunocompetent individuals. For patients receiving regimens that include anti–B-cell antibodies, vaccinations should be delayed at least 6 months.

PEDALL-C (4 of 14)

• Methotrexate (MTX) Toxicity Management
  • 4th bullet added: Doses of leucovorin >25 mg should be given IV due to saturable absorption when given orally.

PEDALL-C (5 of 14)

• Mucositis
  • Prevention, 3rd bullet: Bland rinses such as 0.9% saline solution, sodium bicarbonate, or artificial saliva products Biotene mouthwash (non-alcoholic and unsweetened) should be used twice daily and after meals.

PEDALL-C (6 of 14)

• Steroid Management
  • 2nd bullet, 2nd sub bullet, 1st sub sub bullet removed: Consider hydrocortisone (10 mg/m²/day) with dexamethasone.
• PRES
  • 1st sub sub bullet modified: Anti-hypertensive therapy as needed to maintain blood pressure in age-appropriate range. Avoid calcium channel blockers if possible due to increased risk of hemorrhage. Typically occurs in setting of hypertension in first months of treatment.

PEDALL-C (8 of 14)

• Thiopurines Management
  • 1st bullet, 4th sub bullet modified: For patients with significant gastrointestinal (GI) symptoms (ie, nausea, vomiting) and/or grade 4 alanine transaminase (ALT), aspartate transaminase (AST) and/or direct bilirubin >2 mg/dL, and/or hypoglycemia, consider obtaining mercaptopurine metabolites. For In patients with elevated methylated metabolites and ANC indicating that the dose of 6-MP should be increased, or for those with GI toxicity or hypoglycemia that are dose limiting, consider the addition of allopurinol 50 mg/m² with a 50%–75% decreased dose of 6-MP. Careful ANC monitoring should be considered with this approach, as the interaction of 6-MP and allopurinol carries a significant risk of myelosuppression.

PEDALL-C (9 of 14)

• Behavior and Psychosocial Support
  • 2nd bullet modified: Neurocognitive monitoring during therapy and after completion of therapy should be considered for all patients, given established risk for neurocognitive late effects associated with CNS-directed IT chemotherapy.

PEDALL-C (10 of 14)

• Asparaginase Toxicity Management changed to Asparaginase Therapy
  • 8th Bullet moved here from Hypersensitivity, Allergy, and Anaphylaxis section: Therapeutic drug monitoring (TDM) for asparaginase therapy using the serum asparaginase activity (SAA) is available as a CLIA-certified test with a turnaround time of <1 week, allowing for real-time decision-making and therapeutic adjustments. Generally accepted SAA assay targets include a minimum trough of ≥0.1 IU/mL. However, data indicate that when SAA levels fall below 0.4 IU/mL, asparagine is no longer completely depleted and begins to rebound, suggesting an optimal trough of ≥0.4 IU/mL. Modifications in asparaginase dose or schedule depend on the clinical context.

PEDALL-C (11 of 14)

• Hepatotoxicity (elevation in bilirubin, AST, ALT)
  • 2nd bullet added: Calaspargase, when combined with chemotherapy, has been associated with severe, life-threatening, and potentially fatal instances of SOS. Calaspargase should not be administered to patients with severe hepatic impairment.

PEDALL-C (12 of 14)

• New page added on Toxicity Management for Inotuzumab ozogamicin, Blinatumomab and Tisagenlecleucel

PEDALL-E

• Page heading modified: Special Considerations for Patients with Down Syndrome and Infants Vulnerable Populations
• Down Syndrome Considerations
  • 3rd bullet added: Patients ≥10 years of age receiving blinatumomab should receive seizure prophylaxis for the duration of the blinatumomab cycle.
• Infant Considerations
  • 1st bullet modified: Respiratory syncytial virus (RSV) prophylaxis with a single dose of nirsevimab IM or monthly palivizumab IM monthly should be considered before the onset of and continued through the RSV season.

PEDALL-F (1 of 3)

• Footnote d modified: At Day 10 of Induction IA, based on results of FISH, karyotype, and Rapid Heme Panel (targeted fusion sequencing panel), "Initial Risk Group" is assigned.

PEDALL-F (2 of 3)

• Post-Induction Therapy Risk Group Stratification
  • COG Initial High Risk (B-ALL only):
    • Average Risk added: N/A
  • High Risk, 6th bullet modified: CNS-3 or testicular disease

PEDALL-G (2 of 13)

• Footnote i added: The Panel believes it is reasonable to use bortezomib with BFM backbone chemotherapy in patients with pediatric T-LL, because it was shown to improve EFS/OS in T-LL but not leukemia (Teachey DT, et al. J Clin Oncol 2022;40:2106-2118). (Also for PEDALL-G 6A of 13)
• Footnote j added: It is reasonable to transition patients treated with AALL1231 induction to the AALL0434 backbone with nelarabine post-induction.

PEDALL-G (8 of 13)

• Regimens for Relapsed/Refractory ALL
  • Other Recommended Regimens: Ponatanib added as a category 2B TKI option to consider

PEDALL-G (10 of 13)

• CD19-targeting CAR T-Cell Therapy
  • Tisagenlecleucel, 7th bullet modified: The role of consolidative allogeneic HCT following tisagenlecleucel is unclear. Persistence of tisagenlecleucel (persistence of B-cell aplasia) and negative NGS MRD have has been associated with durable clinical responses without subsequent HCT.

PEDALL-H

• This section was extensively updated.

PEDALL-I

• Response Criteria for Blood and Bone Marrow:
  • 1st bullet, 2nd sub bullet modified: Marrow with trilineage hematopoiesis (TLH) and <5% blasts (M1) or <1% blasts by flow or molecular testing

PEDALL-J (1 of 2)

• 7th bullet, 1st sub bullet, 3rd sub sub bullet added: Prior to HCT.

PEDALL-K (1 of 5)

• Indications for HCT (B-cell) in First Remission:
  • 3rd bullet, 2nd sub bullet modified: HCT is not routinely indicated for BCR::ABL1Ph+ ALL in CR1 (while on TKI plus systemic chemotherapy) provided that the patient has achieved MRD negativity (<0.01%) post-consolidation and is being treated on an intensive pediatric regimen plus TKI. Consider HCT (for BCR::ABL1+ ALL) if relapse (any time point), or MRD ≥0.01% (by week 9–12).
• Footnote removed: Ph+ ALL in CR1 does not require HCT provided that the patient is MRD negative (<0.01%) post-consolidation and being treated on an intensive pediatric regimen plus TKI. Consider HCT (for Ph+ ALL) if relapse (any time point), or MRD ≥0.01% (by week 9–12).

PEDALL-K (2 of 5)

• Footnote c modified: For late bone marrow or isolated extramedullary relapses, if patient achieves MRD-negative CR2 with reinduction/therapy for relapsed disease salvage therapy, no HCT is indicated.
• Footnote d modified: The recommendations may differ based on the treatment regimen. Consideration of HCT can also be made in the setting of MRD of 0.01%–0.09% given an increased risk of relapse. Hogan LE, et al. J Clin Oncol 2023;41:4118-4129; Parker C, et al. Lancet 2010;376:2009-2017.

PEDALL-K (3 of 5)

• Principles of Hematopoietic Cell Transplant
  • Impact of Pre-HCT MRD Status
    • 1st bullet modified: An increased risk of relapse has been noted in children with ≥0.1% MRD pre-HCT for ALL, suggesting the need to attain an MRD level <0.1% prior to HCT. An increased risk of relapse has also been noted in children with an MRD of 0.01%–0.09%.

 

For the complete updated versions of the NCCN Guidelines, NCCN Guidelines with NCCN Evidence Blocks™, the NCCN Drugs & Biologics Compendium (NCCN Compendium^®), the NCCN Biomarkers Compendium^®, the NCCN Chemotherapy Order Templates (NCCN Templates^®), the NCCN Radiation Therapy Compendium™, and the NCCN Imaging Appropriate Use Criteria (NCCN Imaging AUC™), please visit NCCN.org.

To view the NCCN Guidelines for Patients^®, please visit NCCN.org/patientguidelines.

Free NCCN Guidelines apps for iPhone, iPad, and Android devices are now available! Visit NCCN.org/apps.

About NCCN Flash Updates™

NCCN Flash Updates™ is a subscription service from NCCN that provides timely notification of updated and new information appearing in the NCCN Guidelines, the NCCN Compendium^®, and other NCCN Content.

Subscribe to NCCN Flash Updates™

Third Party Content: The NCCN Content may contain content (such as figures, tables or illustrations) that NCCN licenses from third parties as displayed on NCCN Third Party Content site: private.filesanywhere.com/fs/v.aspx?v=8a6d65cfa19ea4bda0a3&C=6241. Licensee shall be solely responsible for obtaining permissions from each such third party to use any such Third Party Content in the Permitted Works. 

Access information on permissions and licensing of NCCN Content

Users may unsubscribe from Flash Updates at any time by contacting us. NOTE: The subscription fee for NCCN Flash Updates™ is non-refundable.