A Pediatric Regimen Is Effective for Adolescents and Young Adults With ALL

Adolescents and young adults (AYAs) with newly diagnosed acute lymphocytic leukemia (ALL) who received a pediatric-inspired regimen had better survival outcomes than historical controls, according to results from the prospective CALGB 10403 study. The findings, which were published in Blood, suggest that AYA patients may benefit from being treated like “old children” rather than “young adults.”

“Given the improvement in survival compared with historical CALGB controls and other recently published studies from both the U.S. and European cooperative groups, we believe that an intensified pediatric regimen should be the basis for future trials designed to further improve survival rates for young adults with ALL,” lead author Wendy Stock, MD, from the University of Chicago Comprehensive Cancer Center, told ASH Clinical News.

The CALGB 10403 study was a multicenter trial involving more than 70 participating institutions throughout the U.S. Between November 2002 and September 2012, 318 AYA patients (age range = 17-39 years) with newly diagnosed B- or T-precursor ALL were enrolled. All participants had an Eastern Cooperative Oncology Group performance status of ≤2 and no prior treatment for ALL (except emergency therapy with corticosteroids or hydroxyurea for hyperleukocytosis, superior vena cava syndrome, or renal failure associated with leukemic infiltration of the kidneys). Patients with Philadelphia chromosome (Ph)–positive ALL were excluded.

A total of 295 patients were eligible for treatment and evaluable for response. Median age among this group was 24 years (range = 17-39). Treatment followed the CALGB 10403 protocol and consisted of induction, consolidation, interim maintenance, delayed intensification, and long-term maintenance therapy with a vincristine, daunorubicin, pegaspargase, and prednisone-based approach.

Approximately 89 percent of patients (n=263) achieved a complete bone marrow response by either the end of induction or following the extension of induction therapy. Allogeneic hematopoietic cell transplantation was performed in 20 patients who achieved remission.

At a median follow-up of 64 months (range = 0.4-109.5), 64 percent of patients (n=190) were alive. The median overall survival (OS) was not reached and the three-year OS rate was 73 percent. This compared favorably with historical controls of patients aged 16 to 29 years with B- or T-precursor ALL, in which median OS was estimated to be 61 months (range = 39-89) and the three-year OS rate was 58 percent (p values not reported).

See the TABLE for other survival endpoints.

Ninety patients had a disease relapse during or after therapy; median post-relapse survival was 10 months (range = 7.0-14) and the three-year survival rate was 23 percent.

The authors also conducted a multivariable analysis to determine which pre-treatment patient and disease characteristics (including age, sex, body mass index, white blood cell count, and cytogenetics) predicted survival outcomes.

The only factors predictive of a survival outcome were obesity and aberrant CRLF2 expression, which were both associated with worse disease-free survival (DFS):

  • obesity (hazard ratio [HR] = 1.82; p=0.04)
  • Ph-like signature/CRLF2 expression (HR=2.84; p<0.001)

In addition, among the 80 patients who had minimal residual disease (MRD) measurements available, MRD-negativity was associated with improved three-year DFS, compared with patients with detectable MRD (85% vs. 54%; p=0.001).

The authors reported eight treatment-related deaths during the study, for a treatment-related mortality rate of 3 percent. “This was low and similar to those reported in pediatric trials of ALL,” they noted. However, “there was a higher incidence of hepatic and thrombotic complications during induction therapy compared with what has previously been reported in younger patients with ALL.”

The most common grade ≥3 adverse events (reported in >10% of patients) during the induction phase included:

  • hypofibrinogenemia (42%)
  • hyperglycemia (31%)
  • elevated transaminases (28%)
  • febrile neutropenia (22%)
  • infection (19%)
  • elevated bilirubin (18%)

“While the regimen was safe …certain chemotherapy-related toxicities remain a challenge,” Dr. Stock said, particularly in obese patients with a body mass index of >40, where survival rates were significantly worse than in other patients. “As we move forward in the next U.S. intergroup study for B-lineage ALL, our goal is to further improve event-free survival (EFS) by testing the addition of the new immune-conjugate, inotuzumab ozogamicin, to enhance early eradication of MRD and to evaluate its impact on Ph-like ALL.” To address improvements in EFS, Dr. Stock referenced the A041501 trial, which is now enrolling patients.

Because this study included only patients up to age 40 years, the findings may be limited in generalizability across the older patient population. However, the researchers report that such an intensive pediatric regimen may increase the rate of toxicities in older patients, which may result in compliance difficulties.

“A large challenge [in future research] will be to evaluate new agents that might further improve survival for our patients with T-ALL, particularly for those high-risk patients with early T-precursor ALL,” Dr. Stock concluded.

The authors report no relevant relationships; the trial was supported in part by Leadiant Biosciences.


Reference

Stock W, Luger SM, Advani AS, et al. A pediatric treatment regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403 (Alliance). Blood. 2019 January 19. [Epub ahead of print]

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