NCCN Update to ALL Guideline Places Greater Emphasis on Philadelphia Chromosome Status


The National Comprehensive Cancer Network has updated its guidelines on ALL in adolescents and young adults.

National Comprehensive Cancer Network (NCCN) Guidelines for acute lymphoblastic leukemia (ALL) have been updated to put a greater focus on the differences between the management of Ph-positive and PH-negative ALL in adolescents and young adults.

“The cure rates and survival outcomes for patients with ALL have improved dramatically over the past several decades, primarily among children. Improvements are largely owed to advances in the understanding of the molecular genetics and pathogenesis of the disease, the incorporation of measurable residual disease testing, the refinement of risk-adapted treatment algorithms, the advent of new targeted agents, and the use of allogeneic hematopoietic stem cell transplantation,” wrote study authors led by Patrick A. Brown, MD.

An analysis of the Surveillance, Epidemiology, and End Results (SEER) database found that the 5-year overall survival rate for children and adolescents is 89% and 61% for young adults. However, 5-years ALL survival rates remain low at 20% to 40%. For older adults, the 5-year OS rate is approximately 20%.

When ALL is suspected, a complete workup should be conducted and include a complete blood count with platelets and differential, a blood chemistry profile, liver function tests, a disseminated intravascular coagulation panel, and a tumor lysis syndrome panel, according to the NCCN Clinical Practice Guidelines. Additionally, appropriate imaging studies should be conducted.

Management of Ph-Positive ALL

While Ph-positive ALL is rare in children, occurring at a rate of approximately 3%, it occurs in 25% of adult cases. In adolescent and young adult patients, the standard of care is hematopoietic cell transplant. The 7-year overall survival (OS) for patients treated with hematopoietic cell transplant between 1995 and 2005 stood at 45%, with the 7-year event-free survival (EFS) standing at 32%.

However, its place has been called into question with the advent of BCR-ABL-targeted tyrosine kinase inhibitors (TKIs). Combining stem cell transplant with immunotherapy may prove to have additional benefit. According to the guidelines, stem cell transplant remains the standard of care for this population.

The COG AALL-0031 (NCT00022737) treatment regimen has also proven to be promising for high-risk patients with Ph-positive ALL. During the trial, 92 patients aged 1 to 21 years old were treated with an intensive chemotherapy regimen combination with 340 mg/m2/day of imatinib during the post remission induction period and during the maintenance period. The 3-year EFS rate was 80.5% (95% CI,64.5-89.8).

In newly diagnosed Ph-positive patients, blinatumomab in combination with ponatinib has also been evaluated in a study of 28 patients with newly diagnosed or relapsed/refractory Ph-positive ALL. The overall response rate was 95%, and the 1-year OS and EFS rate at 100%. Additionally, the regimen was found to have a manageable safety profile.2

TKIs and other non-chemotherapy agents remain an important treatment option in Ph-Positive ALL, according to the guidelines. Bone marrow transplant remains the only cure for relapsed/refractory ALL, however, many patients remain ineligible.

Management of Ph-Negative ALL 

Like in Ph-positive cases, hematopoietic cell transplant remains the standard of care for patients with high-risk disease in first complete response.

The best induction regimen for transplant remains unclear, however. Many different strategies have found to be beneficial in pediatric patients. For example, the PETHEMA ALL-96 regimen (NCT00494897) found that frontline therapy with a 5-drug induction regimen (vincristine, daunorubicin, prednisone, L-asparaginase, and cyclophosphamide), along with triple intrathecal therapy throughout the treatment period, had a 6-year EFS of 61% and a 6-year OS of 69%. No difference in EFS rates were seen in younger adults and adolescents.

The GRAALL-2005 regimen (NCT00327678) found that an induction regimen of vincristine, daunorubicin, prednisone, L-asparaginase, and cyclophosphamide in adolescents and adults with Ph-negative ALL caused an EFS rate of 55% at 42 months.

Chemotherapy was delayed in 1.5% of evaluable patients in the induction cohort, 35% of patients in the first complete remission cohort, 18% of patients in the second complete remission cohort, and 25% of patients in the maintenance cohort. Common adverse events included neutropenia (82%, 59%, 46%, and 10%, respectively), thrombocytopenia (40%, 14%, 2%, and 0%), and coagulation disorders (13%, 2%, 2%, and 0%).3

Blinatumomab (Blincyto) has shown a promising clinical efficacy in this space as well, according to Brown et al. At a median follow-up of 33 months, the relapse-free survival was 61% in the evaluable cohort. However, blinatumomab has been further explored in the release setting, along with other immunotherapies.

Additionally, hematopoietic cell transplant remains the only potentially curative modality for relapsed/refractory ALL. It is recommended over chemotherapy alone in adult patients experiencing a second complete remission. Additionally, several studies have found that it is also beneficial for adolescent and young adult patients in their second remission.

Brown PA, Shah B, Advani A, et al. Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021;19(9):1079-1109. doi:10.6004/jnccn.2021.0042
Slayton W, Schultz K, Kairalla J, et al. Dasatinib plus intensive chemotherapy in children, adolescents, and young adults with Philadelphia chromosome–positive acute lymphoblastic leukemia: results of children’s oncology group trial AALL0622. J Clin Oncol. 2018;36(22):23960-2314.
Ribera JM, Morgades M, Montesinos P, et al. A pediatric regimen for adolescents and young adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: Results of the ALLRE08 PETHEMA trial. Cancer Med. 2020;9(7):2317-2329. doi:10.1002/cam4.2814
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