CancerNetwork® Inaugural Face-Off - Episode 6
Varun Narendra, MD, presents the CALGB 10403 clinical trial on the use of a pediatric regimen in older adolescents and young adults with ALL.
Steven Frommeyer: At this point, I’d like to ask the Mavericks to begin their presentations. Give it your best shot.
Jae Park, MD: The second speaker from the MSK [Memorial Sloan Kettering Cancer Center] team is Varun Narendra. He’s our third-year fellow and we’re especially grateful to have him because he’s more laboratory-focused and is studying TP53 biology there. But he was nice enough to agree [to participate]. He’s an expert in lymphoid and myeloid malignancies, going back and forth. It’s very exciting to have him joining us.
Varun Narendra, MD: Thank you, it’s exciting to be here. Thank you for the invitation. I’m going to be presenting a study that’s been referenced multiple times. This is the CALGB 10403 study that was published in 2019 in Blood by Wendy Stock, [MD,] and colleagues. This has been brought up previously, but motivation for this study was that a number of retrospective analyses at multiple institutions across the world essentially noticed that age-matched cohorts of patients who had been enrolled on clinical trials as part of pediatric vs adult cooperative group studies had markedly different outcomes.
On the left, you see survival curves for patients in United States cooperative groups who were enrolled in adult vs pediatric studies. There are a number of explanations for why this might be, one of which through multivariate analysis was thought to be related to clear differences in the regimens that age-matched patients were receiving when on adult vs pediatric clinical trials.
Specifically, pediatric regimens emphasized nonmyelosuppressive agents, such as PEG-asparaginase, steroids, and higher doses of vincristine, while sharing equivalent dosing of myelosuppressive agents. Moreover, pediatric regimens were tailored toward higher rates of relapse among males, so maintenance regimens were continued for often 3 years in male patients in pediatric clinical trials. Pediatric regimens used more intensive IT [intrathecal] prophylaxis to prevent CNS [central nervous system] relapse as well as a number of other smaller differences. Those findings were the inspiration for translating a pediatric approach to AYA [adolescent and young adult] patients who were in the age range of 18 to 39, as was done in the CALGB 10403 trial.
This was a very large prospective study for patients ages 17 to 39 with newly diagnosed Ph [Philadelphia chromosome]–negative B-cell or T-cell ALL [acute lymphoblastic leukemia]. It was a nonrandomized, single-arm phase 2 study. It enrolled patients across 3 cooperative groups: CALGB, ECOG, and SWOG. The primary end point from this study was event-free survival, disease-free survival, overall survival, and that was compared with historical controls.
To give you a sense of the actual regimen, CALGB 10403 is a 5-course regimen, starting with phase 1 induction. That includes both myelosuppressive and nonmyelosuppressive agents, with a second extended induction phase for patients not achieving M0 or M1 marrow or less than 5% blasts. That’s followed by a consolidated phase, and then course 3 is interim maintenance characterized by the use of Capizzi methotrexate, which is a dose-escalating methotrexate without leucovorin rescue. Course 4 is delayed intensification, which is more unique to pediatric regimens. Course 5 is maintenance, again stratified by sex. Men complete 3 years of maintenance therapy vs women who complete 2 years.
The study showed pretty good efficacy compared with historical controls. In the study, 295 patients were followed for a median duration of 64 months, or over 5 years. Complete response rates were quite encouraging, 89% after the cycle course 1 induction. The 3-year overall survival was 73% in the CALGB 10403 study, and that’s compared with 58% when one looks at historical controls. As far as event-free survival, a median of 78.1 months was achieved, compared with 30 months, which was how the study was powered. Disease-free survival among patients who had responded was 81.7 months compared with 34 months.
Some other notes about the study: it was largely a transplant-free treatment course for these patients. Only 20 patients underwent allogeneic transplant in CR1 [first complete remission]. Those were largely patients with t(4;11) or hypodiploid ALL. Importantly, age range itself wasn’t associated with response, meaning patients who were 20 to 29 didn’t achieve higher rates of response than those 30 to 39, suggesting strong activity in the older subgroup. Predictive factors include white blood cell count greater than 30,000 per μL at diagnosis; obesity, particularly BMI [body mass index] of over 40; the presence of Ph–like disease; RNA; CRLF; and relatedly, CRLF2 positivity.
With respect to MRD [minimal residual disease] that’s been discussed, there’s a very clear difference in disease-free survival among responders who achieved MRD negativity vs positivity. MRD was defined by RT-qPCR [quantitative reverse transcription polymerase chain reaction] of the immunoglobulin heavy chain or the TCR [T-cell receptor] with a sensitivity of 10-4., and 44% of patients achieved MRD negativity, which is lower than what was typically seen among pediatric patients. You can see 3-year disease-free survival being in the 80th percentile range for patients who are MRD negative compared with roughly 54% in the MRD positive.
One concern about pediatric-inspired approaches with older patients is toxicity from drugs like PEG-asparaginase, but those were generally manageable. Importantly, the overall treatment-related mortality was just 3%, which is similar to what had been seen in pediatric patients. In terms of grade 3/4 toxicities, I’ll focus on the PEG toxicities, with 10% hypersensitivity reactions to the PEG-asparaginase. That was improved when they adjusted the protocol to use prophylaxis against hypersensitivity reactions. Hypertriglyceridemia was at 11%. Hyperbilirubinemia was around 18%. Pancreatitis was around 5%. Hyperfibrinogenemia was 42%, but rarely did that lead to significant hemorrhage. Just 1 patient had CNS hemorrhage in the study.
Overall, the takeaways are that, as Dr Mato said, this is a very safe and efficacious regimen for patients up to age 40 on the study. It seems to be pretty active, even in the 30 to 39 subgroup. MRD status is clearly prognostic in this case. The MRD negative clearance was not as high as I expected, but patients who achieved MRD negativity did quite well. One major outstanding question is, if one were to incorporate novel agents into a CALGB 10403 regimen, how would that affect outcomes? Particularly with a goal of achieving either earlier or higher rates of MRD negativity. That’s an outstanding question and the impetus for an ongoing Alliance trial to try to incorporate drugs such as inotuzumab into CALGB 10403.
Transcript edited for clarity.