NCCN Guidelines Set New Pace for Pediatric ALL

Publication
Article
Oncology Live®Vol. 20/No. 15
Volume 20
Issue 15

With the recent publication of an inaugural set of guidelines for treatment of pediatric acute lymphoblastic leukemia, the National Comprehensive Cancer Network seeks to introduce standards to a branch of care long dominated by clinical trial protocols.

Patrick Brown, MD

Patrick Brown, MD

Patrick Brown, MD

With the recent publication of an inaugural set of guidelines for treatment of pediatric acute lymphoblastic leukemia (ALL), the National Comprehensive Cancer Network (NCCN) seeks to introduce standards to a branch of care long dominated by clinical trial protocols. These new standards are intended for managing different age groups and risk levels, youths with Philadelphia chromosome (Ph)-positive ALL, and toxicities, with an eye toward current and long-term risks of care.1

Each year, ALL, the most common children’s cancer in the United States, affects about 2900 individuals ≤21 years. Although the blood cancer accounts for 35% of all cancers for this age group, cure rates have dramatically improved and treatments have become mainstream, contributing to the transition from clinical trial predominance, according to Patrick Brown, MD, chair of NCCN Guidelines for Adult and Pediatric ALL and director of the Pediatric Leukemia Program at Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland. In the 1960s, the cure rate for pediatric ALL rested at 0%. Today, owing to many key clinical developments, that number has risen to about 90% (Table).2-7 Brown called that one of “the most profound medical success stories in history.”

Two trials in particular, the phase I/II Study MT103-205 (NCT01471782) and the phase II ELIANA trial (NCT02435849), significantly advanced the treatment of pediatric ALL.

The MT103-205 study led to the September 2016 approval of blinatumomab (Blincyto) in patients with Ph-negative, relapsed or refractory (r/r) pediatric ALL. Among 70 patients who received the recommended dosage, the median overall survival was 7.5 months (95% CI, 4.0-11.8).7

In ELIANA, the chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel (Kymriah) demonstrated noteworthy clinical activity in patients ≤25 years with r/r B-cell ALL (B-ALL) for whom all standard treatment options had been ineffective. There were 75 patients who received a tisagenlecleucel infusion and could be evaluated for efficacy. The overall remission rate was 81% within 3 months. Event-free survival and overall survival were 50% and 76%, respectively, at 12-months.6

Because fewer patients participate in randomized clinical trials and physicians work without the protocols imposed by trial sponsors, guidelines that systematize treatment become necessary. “We’ve reached a situation where the proportion of patients for which we can offer clinical trials is decreasing because the outcomes are so good. That was one of the major drivers that led the NCCN to create the guidelines at this time,” Brown said in an interview with OncologyLive®.

Over the past 10 years, about one-third of patients with pediatric ALL have achieved an estimated cure rate that is close to 100% with now-standard therapy. “For these patients, it is no longer feasible to perform a traditional phase III clinical trial that seeks to improve cure rates,” Brown said.

Table. Key Trials and Agents in Evolution of Therapy for Pediatric ALL2-7

An additional reason for the NCCN’s release of the guidelines was the need for authoritative pediatric ALL treatment pathways that would help ensure payer concurrence with treatment methodologies that physicians were selecting, Wui-Jin Koh, MD, chief medical officer of the NCCN, explained. In the adult [ALL] cancer population, where NCCN guidelines [are well established], systemic therapies are covered by payers based on their inclusion in NCCN guidelines. We had heard from many pediatric oncologists who said that because NCCN guidelines did not include pediatric tumors, they would have to then go back to the insurance companies to justify the use [of certain drugs] and essentially spend time dealing with all those insurance/regulatory issues. [The] NCCN is so well accepted that if it is in NCCN guidelines, in general it is used for coverage determinations by multiple payers,” Koh said.

An example of an agent that represents a payment obstacle is tisagenlecleucel. With a cost of $475,000 for a single dose and ancillary treatment and hospitalization costs that could push the total much higher, tisagenlecleucel evokes much concern among payers, patient advocates, and physicians. CAR T-cell coverage is currently the focus of a protracted CMS payment policy review.8 Nevertheless, CAR T-cell therapy and other immunotherapies hold potential for dramatically improved outcomes in pediatric ALL.

Patients with pediatric ALL typically complete a treatment regimen that spans 2 to 3 years. Treatment includes multiagent chemotherapy regimens, as well as 4 other components: remission induction, consolidation, maintenance, and central nervous system—directed therapy. The NCCN’s guidelines generalize treatment procedures for those in whom pediatric ALL is diagnosed from birth through young adulthood. The guidelines categorize the NCCN’s treatment recommendations by risk level. The highest-risk patients are those whose ALL is diagnosed in the first 12 months of life and who are aged 10 to 21 years.

In addition to outlining chemotherapy for treatment of pediatric ALL, the NCCN guidelines address recent developments in immunotherapy and suggest methods of incorporating these approaches into treatment patterns. They also contain the “best known evidence” for how to integrate immunotherapies for the treatment of ALL, particularly B-lineage ALL, according to Brown.

The application of novel immunotherapies, however, is but one part of the guidelines’ purview. The guidelines emphasize that highrisk patients be identified and underscore that patients with Down syndrome and very young infants (<1 year) are particularly vulnerable to adverse events (AEs), as these 2 subgroups are more likely to encounter AEs than others with pediatric ALL. The NCCN sought to recommend specific enhanced supportive care measures and labored to prescribe therapeutic adjustments that have shown to be effective in managing the increased risk of toxicity among these susceptible subgroups. “It’s not a matter of just adding more and more [treatment],” Koh said. “When you get to a certain level, you need to start asking where you can subtract, with the notion of not reducing efficacy, but reducing toxicity.”

In the pediatric ALL guidelines, the NCCN also delineates optimal treatment options for patients with Ph-like ALL, which accounts for up to 15% of childhood B-ALL. Patients with PH-positive ALL are eligible for treatment that relies on tyrosine kinase inhibitors (TKIs) that target the chromosomal abnormality. Brown notes that another subset of patients with ALL was recently found to display a genetic aberration similar to the Philadelphia chromosome. These patients, Brown said, can also benefit from TKIs and make up the Ph-like subset of ALL. The NCCN’s guidelines also incorporate recommendations for how to diagnose and treat this subset.

The concept of guidelines for pediatric ALL cancer is not entirely new to the NCCN. The alliance first proposed a limited number of guidelines for the treatment of patients with pediatric cancers in the late 1990s, but ultimately halted the project, given that most childhood cancers in the United States were then treated according to the individual protocols of clinical studies. The NCCN now intends to develop guidelines for at least 90% of all incident childhood cancers. The next will be for pediatric Burkitt lymphoma.

The new guidelines for pediatric ALL also reflect the NCCN’s rising influence in the past 2 to 3 years as a global authority on cancer treatment. “In many parts of the world, they don’t have the luxury of having subspecialists like pediatric oncologists like we do here in North America, so childhood cancers are treated by general oncologists who may not have specific training in pediatric cancers,” Koh said. “In our [international] efforts, especially in sub- Saharan Africa, [we’ve been asked to provide] guidance in treating pediatric cancers.”

Before it unveils guidelines for the treatment of pediatric Burkitt lymphoma, the NCCN will first roll out resource-stratified guidelines for pediatric ALL. These guidelines will suggest courses of treatment that are appropriate for parts of the world where certain therapies or diagnostic technologies may not be available, according to Brown. These guidelines will enable oncologists in low- and middle-income countries to safely administer curative treatment for pediatric ALL using the resources available to them. Brown hopes to publish this specialized set of guidelines in the next 3 to 4 months.

The publication of NCCN guidelines for pediatric ALL follows the 2012 first release of NCCN guidelines for adult ALL treatment. The impetus for that earlier set of standards was the realization that patients aged 15 to 39 years can tolerate the more intensive regimens used for children. That set of guidelines also addressed treatment for adults ≥65 years with ALL, who tend to have more cytogenetic abnormalities as well as Ph-positive ALL, which carries a poor prognosis and requires patient stratification.

The adult and pediatric ALL guidelines dovetail in that both sets recommend pediatric or “pediatric-inspired” treatment paths for the adult and young adolescent (AYA) patient population. AYA patients with ALL might either see a pediatric oncologist or a medical oncologist when they first seek medical care; the overlap of the adult and pediatric ALL guidelines promotes consistency and ensures that these patients can receive the best treatment. “Clinical evidence demonstrates that outcomes for AYA patients with ALL are best when they are treated with so-called ‘pediatric-inspired’ treatment protocols, regardless of whether they are treated in a pediatric or adult setting,” Brown said.

References

  1. New NCCN guidelines for children with cancer meet growing needs of pediatric oncology community worldwide [news release]. Plymouth Meeting, PA: National Comprehensive Cancer Network; May 30, 2019. prnewswire.co.uk/news-releases/new-nccn-guidelines-for-children-with-cancer-meet-growing-needs-of-pediatric-oncology-community-worldwide-806025670.html. Accessed July 9, 2019.
  2. Aur RJ, Simone J, Hustu HO, et al. Central nervous system therapy and combination chemotherapy of childhood lymphocytic leukemia. Blood. 1971;37(3):272-281.
  3. Clavell LA, Gelber RD, Cohen HJ, et al. Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med. 1986;315(11):657-663. doi: 10.1056/NEJM198609113151101.
  4. Schultz KR, Bowman WP, Aledo A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children’s oncology group study. J Clin Oncol. 2009;27(31):5175-5181. doi: 10.1200/JCO.2008.21.2514.
  5. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia [erratum in N Engl J Med. 2016;374(10):998. doi: 10.1056/NEJMx160005]. N Engl J Med. 2013;368(16):1509-1518. doi: 10.1056/NEJMoa1215134.
  6. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi: 10.1056/NEJMoa1709866.
  7. von Stackelberg A, Locatelli F, Zugmaier G, et al. Phase I/phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. J Clin Oncol. 2016;34(36):4381-4389. doi: 10.1200/JCO.2016.67.3301.
  8. CMS statement: delay in final chimeric antigen receptor (CAR) T-cell therapy national coverage determination [news release]. Baltimore, MD: Centers for Medicare & Medicaid Services; May 17, 2019. cms.gov/newsroom/press-releases/cms-statement-delay-final-chimeric-antigen-receptor-car-t-cell-therapy-national-coverage. Accessed July 9, 2019.
Related Videos
Corey Cutler, MD, MPH, and Hana Safah, MD, experts on GvHD
Guenther Koehne, MD, PhD
Lori A. Leslie, MD, an expert on lymphoma
Lori A. Leslie, MD, an expert on lymphoma
A panel of 4 experts on MDS
Elias Jabbour, MD
Corey Cutler, MD, MPH, and Hana Safah, MD, experts on GvHD
Corey Cutler, MD, MPH, and Hana Safah, MD, experts on GvHD