A pediatric-based protocol has delivered promising preliminary results in adults with acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), according to data presented at the 2021 American Society of Hematology (ASH) Annual Meeting & Exposition.1 Findings from the large, population-based GMALL trial showed that pediatric-based chemotherapy in combination with risk-adapted stem cell transplantation and targeted therapies was feasible and effective not only in adolescents and young adults, but in the whole group of adult patients with ALL up to age 55. Intensive and individualized asparaginase treatment was also feasible in a large multicenter setting, authors of the study reported.
“With a pediatric-based protocol, 93% of study patients showed a complete response after consolidation, and the complete response rates were high throughout all subgroups,” said lead study author Nicola Goekbuget, MD, of Goethe University Hospital, Frankfurt, Germany. “Only in high-risk patients was a slightly decreased complete response rate observed.”
Nicola Goekbuget, MD
According to Dr. Goekbuget, tremendous progress has been made with respect to outcomes for adults with ALL over the past decades. In particular, the outcomes of younger adults are now comparable to those of adolescent-centered pediatric protocols. Despite improved first-line therapies, however, challenges remain, including age cutoffs for protocols without clear rationale.
In addition, although chemotherapy is essential for cure, said Dr. Goekbuget, there are limitations because of acute and late toxicities. There are also nonsatisfactory results in patients with measurable residual disease (MRD) and relapsed or refractory disease.
“We need to further optimize standard chemotherapy compounds in adults and integrate new, targeted compounds earlier during the treatment algorithm,” said Dr. Goekbuget.
Dr. Goekbuget and colleagues designed the GMALL trial to study the use of a pediatric-based protocol in adults (aged 18–55 years) with newly diagnosed ALL and LBL. Between 2007 and 2021, the investigators recruited 770 patients from 78 centers, including all large and medium-sized centers treating adult ALL in Germany.
The trial had limited exclusion criteria, said Dr. Goekbuget. However, of note, it did not allow any relevant pretreatment of ALL besides prephase and a single application of a cytostatic drug.
Features of the trial include the following: targeted therapy for molecular failure and molecular relapse, optimized standard therapy via intensification of asparaginase, a new induction for Philadelphia chromosome–positive (Ph+) ALL, and nelarabine in first-line consolidation for T-lineage ALL.
The protocol consists of pediatric-based chemotherapy with dexamethasone, up to eight cycles of PEG-asparaginase with high-dose methotrexate, a reinduction regimen, and conventional maintenance up to 2.5 years. Two cycles of nelarabine are implemented for standard risk T-lineage ALL. The protocol also has a risk-based transplant indication with conventional risk factors for historical comparability and molecular failure after consolidation. The primary endpoint of the trial is event-free survival.
“It remains our goal to improve the outcomes of ALL in a broad population base and not just to test specific drugs,” said Dr. Goekbuget.
Complete Responses Across All Subgroups
As Dr. Goekbuget reported, preliminary results showed that 93% of patients achieved a complete response after consolidation, and the complete response rates were high across all subgroups. Approximately 4% of patients died during induction.
“We’ve observed a similar rate [of mortality] throughout all of our trials,” said Dr. Goekbuget. “This potentially represents the inherent risk of severe infection in a large, unselected patient population.”
Whereas hematologic complete response was evenly distributed across subgroups, a larger difference was observed for molecular response. “Patients with higher-risk features and patients with Ph+ ALL had higher rates of molecular failure and higher rates of low-positive MRD,” said Dr. Goekbuget. “However, this regimen, specifically designed for Ph+ disease, is excellent and compares favorably with other trials.”
In addition, Dr. Goekbuget highlighted the success of intensive and individualized PEG-asparaginase treatment. The first dose (2,000 U/m2) was administered at the end of induction phase one, when patients were in stable condition. The second dose was recommended only in patients without relevant toxicities from the prior dose.
“Overall, the individualized asparaginase therapy became more and more feasible for the whole protocol,” said Dr. Goekbuget. “We have, however, observed several osteonecrosis cases in younger patients and therefore initiated a new management protocol for this complication.”
Dr. Goekbuget also reported that the MRD-based targeted therapy was realized in a high percentage of patients with molecular failure (90%). However, the molecular response rate for blinatumomab was 55%, said Dr. Goekbuget, which is lower than in previous trials. The molecular response rate to nelarabine in T-cell ALL was 18%.
“This shows that we must look for alternatives for patients with T-cell ALL,” said Dr. Goekbuget. “However, the overall survival of patients who experienced molecular failure is promising with the combination of targeted therapy and stem cell transplantation. Transplantation is still a key component, although the overall proportion of transplantation was lower than the previous GMALL trials,” she concluded.
DISCLOSURE: Dr. Goekbuget reported financial relationships with AbbVie, Servier, AstraZeneca, Amgen, Jazz Pharmaceuticals, Pfizer, Incyte, Novartis, MorphoSys, Erytech, Cellestia, and Gilead/Kite.
1. Goekbuget N, Stelljes M, Viardot A, et al: First results of the risk-adapted, MRD-stratified GMALL Trial 08/2013 in 705 adults with newly diagnosed acute lymphoblastic leukemia/lymphoma. 2021 ASH Annual Meeting & Exposition. Abstract 362. Presented December 12, 2021.
In an interview with The ASCO Post, Hanno R. Hock, MD, PhD, Assistant Professor of Medicine at Harvard Medical School and Massachusetts General Hospital, highlighted the study’s “very nice response rate” and “encouraging data” while also noting that a pediatric-based treatment regimen in fit adults ...