Annual Meeting
Photo courtesy of ASH
ORLANDO, FL—Results of a DFCI ALL Consortium trial have shown that adults with acute lymphoblastic leukemia (ALL) can be successfully and safely treated with a pediatric regimen using intensified pegylated asparaginase (PEG-ASP).
Investigators recently reported that young adults treated with native E coli asparaginase as part of their regimen had improved 4-year disease-free survival and overall survival (OS) rates.
Now, the team has shown it is possible to use PEG-ASP to improve young adult outcomes as well.
The investigators also described the toxicities with PEG-ASP and compared them to the prior DFCI ALL Consortium trial with native E coli asparaginase.
“[Wendy] Stock, years ago, analyzed young adult patients 16 to 20 based on whether or not they were treated on Children’s Cancer Group trials or CALGB trials,” said Daniel J. DeAngelo, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
“And what she reported was that there was a dramatic improvement in the disease- and event-free survival . . . . And since that publication and presentation at ASH several years ago, there’ve been a large number of us who’ve tried to adapt pediatric trials or pediatric-inspired trials for the treatment of young adults with acute lymphoblastic leukemia.”
The PEG-ASP DFCI ALL trial is one such effort. Dr DeAngelo discussed the results of this trial at the 2015 ASH Annual Meeting (abstract 80).
Patient population
Investigators enrolled 110 patients on the trial.
Patients had to be between 18 and 50 years of age, with untreated ALL and no history of secondary ALL. Patients with Burkitt’s lymphoma were excluded.
The patients’ median age was 32 (range, 18–50), 62% were male, 80% were white, and 85% were non-Hispanic. Eleven percent had central nervous system (CNS) status 2 or 3 prior to the initiation of chemotherapy.
Most (87%) had a performance status of 0 or 1, 82% had the B-cell and 18% the T-cell phenotype, 19% were Ph-positive, 6% had an MLL translocation (11q23), and 18% had other translocations.
Study design
Induction chemotherapy consisted of doxorubicin, prednisone, vincristine, PEG-ASP, and intrathecal therapy.
The first consolidation consisted of high-dose methotrexate followed by a BFM-like intensification and high-dose cytarabine, etoposide, and dexamethasone.
CNS prophylaxis included intrathecal chemotherapy and cranial irradiation.
The second consolidation consisted of eight 3-week courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine, and 30 weeks of PEG-ASP.
The PEG-ASP was initially dosed at the pediatric level of 2500 IU/m2 every 2 weeks.
“But due to some toxicity concerns in this treatment strategy—with specific emphasis on liver function abnormalities with hyperbilirubinemia, elevations of AST/ALT—we decided to amend the protocol and decrease the PEG dose from 2500 to 2000 and increase the interval from every 2 weeks to every 3 weeks,” Dr DeAngelo said.
Therefore, during this 30-week course, patients received 10 doses of PEG ASP as opposed to 15.
“We also went back and swapped out the PEG asparaginase during induction and reinserted native E coli to really ascertain comparative properties,” he said.
Maintenance therapy consisted of 3-week courses of vincristine, dexamethasone, methotrexate, and 6-mercaptopurine for 2 years from achievement of complete remission (CR).
During PEG-ASP therapy, patients received anticoagulation prophylaxis, preferably with low-molecular-weight heparin, as long as patients had a platelet count greater than 30,000/μL.
Results
Of the 110 patients enrolled, 65 received the higher dose of asparaginase, and 45 received the amended lower dose.
Ninety-one patients (89%) achieved a CR, 57 of whom received the higher dose of asparaginase and 34 the lower dose.
There were 2 induction deaths, both in the higher-dose group.
Twenty-one patients went on to transplant in CR1, 15 in the higher-dose group and 6 in the lower-dose group.
Twenty-three patients relapsed, 17 in the higher-dose group and 6 in the lower-dose group. Two of the relapses were CNS only.
Three patients died in remission, 2 in the higher-dose asparaginase group and 1 in the lower. And 3 patients died after stem cell transplant in CR, 2 in the higher-dose group and 1 in the lower.
At a median follow-up of 42.2 months, the 3-year disease-free survival for the entire cohort was 73%, and overall survival was 75%.
Subset analyses
The investigators performed subgroup analyses and came up with some “interesting observations,” Dr DeAngelo said.
Younger patients, ages 18 to 19 and 20 to 29, had a better OS than the older patients. The OS for younger patients is in the 80% to 85% range, “which is significantly better than the other patients in the 30 to 40 or 40 to 50 age groups,” Dr DeAngelo said.
Patients with T-cell ALL had a better OS than those with B-cell ALL and Ph-positive ALL, who had the worst OS of approximately 50%. The vast majority of Ph-negative patients were transplanted, and all received imatinib in addition to chemotherapy.
“[Patients with the T-cell phenotype] seemed to do particularly well on this strategy, which is something we showed in the last study as well, with an overall survival of 80%, compared to 70% for the B-cell Philadelphia-negative [patients],” Dr DeAngelo said.
He and his colleagues also found an association between OS and body mass index (BMI).
Obese or morbidly obese patients with a BMI of 30 or over had an OS of around 40%, while underweight or normal-weight patients had an OS of almost 90%, a “profound overall survival in the less-than-obese patients,” Dr DeAngelo said.
“And I think one of the things that is bringing down the curves is the obese,” he added, “which is a concern as the body mass index of the American population increases.”
Another discovery was that patients with minimal residual disease (MRD) of less than 10-4 had better OS than those with a high MRD level.
After a single dose of PEG ASP during induction on day 4, asparagine was depleted for a median of 3 weeks. With a single dose of E coli asparaginase, on the other hand, asparagine is depleted for about a week.
Asparaginase levels during consolidation were “extraordinarily elevated” with the 2500 dose level of PEG-ASP compared to the lower dose level. Toxicity was much more manageable, however, as the dose was reduced, Dr DeAngelo said. And asparagine was still depleted throughout the 30 weeks, as per protocol.
Toxicity
The higher asparaginase dose group “surprisingly, had a very low rate of clinical pancreatitis,” Dr DeAngelo said.
At the higher asparaginase dose—2500 IU/m2 every 2 weeks—66 patients experienced grade 3-5 adverse events: 30 (46%) febrile neutropenia, 1 (1%) pancreatitis, 19 (29%) AST, 34 (52%) ALT, 24 (36%) bilirubin, 19 (29%) thrombosis, 2 (3%) CNS hemorrhage, 3 (4%) hypersensitivity, and 4 (6%) osteonecrosis.
After the protocol amendment, “we saw a marked reduction in hyperbilirubinemia,” Dr DeAngelo said.
Grade 3–4 hyperbilirubinemia decreased from 36% to 7%, grade 3–4 ALT elevation decreased from 52% to 29%, and the rate of thrombosis decreased from 29% to 16%.
“Whether the latter decrease [thrombosis] was reflective of the decreased dose of asparaginase or the addition of anticoagulation, I can’t determine,” Dr DeAngelo said, “but it seemed to reflect other studies.”
The investigators concluded that a dose-intensified pediatric regimen in adults is feasible, with an acceptable toxicity profile.
The team said this approach may translate to better survival for adults with ALL, with the exception of older adults and patients with a high BMI. PEG-ASP has increased toxicity in these patients.
The investigators recommend addressing the challenges that remain—psychosocial issues, practice patterns, and biology—with a unified approach and more cooperative group trials in young adults.
