“I am optimistic the future is bright for our patients with this challenging disease.”— Wendy Stock, MD
Three years ago, early results from the U.S. Intergroup C10403 trial,1 which evaluated the effectiveness of treating adolescent and young adults (AYAs) with acute lymphoblastic leukemia (ALL) using an intensive pediatric regimen, showed significant improvement in event-free and overall survival compared with historic controls. According to the study results, patients treated with a pediatric-inspired regimen that included intensified glucocorticoid, vincristine, and pegaspargase (Oncaspar), as well as prolonged maintenance therapy, had a 2-year event-free survival of 66% and a 2-year overall survival of 79% compared with 34% and 39%, respectively, in historic controls.
According to Wendy Stock, MD, lead author of the study, the final survival analysis confirms the feasibility and efficacy of this approach to treatment of ALL in young adults, and a manuscript summarizing the results will soon be submitted for publication.
In a wide-ranging interview with The ASCO Post, Dr. Stock, Co-Director of the Adolescent and Young Adult Cancer Program and Anjuli Seth Nayak Professor in Leukemia at the University of Chicago Medicine, discussed what researchers are learning about the biologic differences in blood cancers in the AYA population compared with younger and older patients; the differences in survival rates; and the launch of a new U.S. intergroup trial—A041501, led by the Alliance for Clinical Trials in Oncology—which will address whether the addition of inotuzumab ozogamycin to the C10403 backbone can eradicate minimal residual disease early during treatment in AYAs with ALL and further improve their outcomes.
Different Treatment Strategies Based on Age
Among your research interests is the identification of new biologic prognostic factors in blood cancers in AYA patients. What are you learning about how blood cancers develop and should be treated in these patients vs in younger and older patients with ALL?
About 9 years ago, researchers in Europe and the United States identified a new subset of ALL called Philadelphia chromosome–like (Ph-like) or BCR-ABL-like. It has a gene-expression profile similar to that in patients with Ph-positive ALL, but it does not have the 9:22 translocation or BCR-ABL-like signature rearrangement. Ph-like or BCR-ABL–like ALL has an activated kinase signature as part of its genetic makeup, but it does not have the BCR-ABL fusion.
Brandon Hayes-Lattin, MD, FACP
It’s a fascinating development because this subset of ALL is found in between 8% and 10% of children, but it makes up almost one-third of young adults—and a similarly high percentage of older adults—with this disease. Ph-like ALL is a whole new subset of disease that had never previously been described, and it has been associated with very poor survival rates, even in pediatric ALL. We have also recently learned a lot about the outcomes of AYAs with this subset of ALL, which is associated with a poorer prognosis with our current state-of-the-art therapies. Even in our C10403 trial, patients with this subtype fared worse than those patients without Ph-like ALL.
This finding helps explain why young adults with ALL have done less well than pediatric patients, even when using pediatric-inspired regimens, because this subset makes up a large percentage of AYAs with ALL. However, because there are a number of activated kinases resulting from cryptic fusions in Ph-like ALL, there is the potential for identifying these patients at diagnosis and targeting their disease with specific kinase inhibitors, and this can be tested prospectively as kinase inhibitors are added to front-line treatments.
Overcoming Discrepancies in Overall Survival
In addition to the Ph-like subset of ALL found in more AYAs than children, what are some of the other factors causing such a discrepancy in overall survival in both age groups, with cure rates among children with the cancer reaching nearly 85%, and the 5-year survival rate for AYAs being just 50%?2
Just that one biologic insight may explain part of the variation in cure rates between the two age groups. The other consideration is that in the past, we treated ALL the same way in adults regardless of whether they were age 18 or 80. In the adult cooperative groups, perhaps because we were familiar with dose intensification for improving outcomes in AML, we focused our efforts on more intensive myelosuppressive therapies for ALL. Despite the dose intensification of daunorubicin and cytarabine in ALL regimens , the survival rates for adults had not improved in successive Cancer and Leukemia Group B (CALGB) studies. In contrast, pediatric protocols intensified the use of nonmyelosuppressive agents, including glucocorticoids, vincristine, and pegaspargase, which has resulted in successive generations of survival improvements.
We then did a comparison survival analysis of AYAs who received pediatric regimens and AYAs who received adult cooperative group regimens and found far better survival rates for AYAs treated on pediatric protocols. This led us to launch the C10403 trial, which was identical to a recent successful pediatric regimen.
Testing New Agents
Have you launched a clinical trial to test the new agents for AYA ALL?
We have designed a trial called A041501, and it has just been activated this month (June 2017). The trial is open only to AYA patients with B-precursor ALL, because the new agent we are studying, inotuzumab ozogamicin, is an antibody-drug conjugate directed against CD22, which is expressed on lymphoblasts of approximately 95% of B-precursor ALL. The hypothesis is that the addition of inotuzumab ozogamicin will improve the rate of minimal residual disease negativity, because we know that early eradication of minimal residual disease is prognostic for prolonged disease-free and overall survival in many trials in both pediatric and adult ALL.
Adopting Pediatric Treatment Approach
Are more oncologists adopting the pediatric-treatment approach you describe in your study for their AYAs with ALL?
We have had very good accrual nationally to the 10403 trial, and given the improvement in survival and the increasing familiarity and comfort with an intensive pediatric regimen for AYA patients among clinical investigators across the country, I believe there is increasing acceptance of this approach.
It is very important that we now again have a national cooperative group trial (A041501) specifically designed for AYAs. That should encourage broad national participation and should provide specific guidance to treating physicians and their patients to promote treatment adherence.
Encouraging Trial Participation
Another reason AYAs with ALL have poorer outcomes is their low participation in clinical trials. What can oncologists do to encourage their AYA patients to enroll in clinical studies?
The challenges for young adults with ALL are many, such as access to medical care, including clinical trials and health insurance, and the duration of treatment, which can go on for 3 years. In the past, barriers to enrollment in clinical studies have included limited availability to clinical studies, but we now have these trials to offer prospectively to patients. So as hematologists/oncologists, we have to do a better job of educating our patients about the potential benefits of participating in clinical trials and the availability of these AYA-specific trials.
Although physicians often refer patients for transplant consideration, they should also consider referring patients for participation in these exciting new front-line trials, which may further improve survival rates and obviate the need for transplantation. With the introduction of the new antibody-drug conjugates and other exciting immunotherapies, including the bispecific T-cell–engaging antibodies, the chimeric antigen receptor T-cell therapies, and the potential for targeted tyrosine kinase inhibitor therapies, this is an extremely exciting time, and I am optimistic the future is bright for our patients with this challenging disease. ■
DISCLOSURE: Dr. Stock reported no conflicts of interest.
1. Stock W, Luger SM, Advani AS, et al: Favorable outcomes for older adolescents and young adults with acute lymphoblastic leukemia: Early results of U.S. Intergroup Trial C10403. 2014 ASH Annual Meeting. Abstract 796.
2. American Cancer Society: Survival Rates in Young Adults With Cancer. Available at www.cancer.org/cancer/cancer-in-young-adults/survival-rates.html. Accessed June 5, 2017.