3 days ago
Emerging Treatment Strategies Benefit Older Adults With ALL
CHICAGO — Acute lymphoblastic leukemia (ALL) remains challenging to treat in older adult patients due to biological factors and poor treatment tolerance. But a variety of treatment approaches beyond chemotherapy-only regimens are making inroads in this challenging disease.
That's the message Elias Jabbour, MD, of MD Anderson Cancer Center in Houston, delivered during an educational session at American Society of Clinical Oncology (ASCO) 2025.
'Our data show that 5-year overall survival (OS) for patients aged 65+ years remains less than 20, despite all the treatment advances we've seen in the past decade,' Jabbour told attendees.
Referring to a review article he co-authored that was published recently in JAMA Oncology , Jabbour noted that these poorer outcomes are due to both disease characteristics and patient characteristics.
Regarding disease characteristics, ALL in older adults is more likely to be of B-cell origin, with a greater co-expression of myeloid antigens. It may also have more adverse cytogenetic abnormalities, including Philadelphia positivity, t(4;11), low hypoploidy/near triploidy. It may also have less high hyperdiploidy, t(12;21), and normal karyotype. These traits make ALL in older adults more refractory to primary chemotherapy, Jabbour said.
Patient characteristics that contribute to poorer outcomes in ALL include lower male to female ratio, reduced renal function, and a tendency to have worse mucositis. A history of cardiovascular disease (CVD) is common, Jabbour said, noting the importance of establishing a baseline ejection fraction before beginning treatment. With an estimated past malignancy rate of 8%-16% in this population, these factors all combine to lead to more early deaths, Jabbour added.
Jabbour noted that immunotherapies like blinatumomab and inotuzumab have shown promise, with similar response rates in older and younger patients. He summarized results from the trials that established immunotherapy as standard of care in relapsed or refractory ALL. Data published in The New England Journal of Medicine (NEJM) in 2017 showed that the median OS for patients in the blinatumomab group was 7.7 months vs 4.0 months for those in the standard chemotherapy group. More patients had a marrow complete response (CR) in the blinatumomab group than in the chemotherapy group, at 44% vs 25%. Data published in the NEJM in 2016 found that patients who received inotuzumab were more likely to have a marrow CR than those in the chemotherapy group (74% vs 31%).
Jabbour also shared data from two studies that stratified patients by age. With blinatumomab, the overall response rate (ORR) was 56% in patients aged 65 years or older compared with 46% in patients younger than 65 years, according to data published in Cancer. Jabbour also shared data from one of his own trials published in Cancer that found that inotuzumab had an ORR of 81% in patients aged 55 years or older vs 80% in those younger than 55 years.
'Then, we asked if we could take these drugs to the frontline and spare the need for intensive chemotherapy for older patients and those with comorbidities,' Jabbour said. 'In 2010, we designed the mini-hyper-CVD regimen with significantly trimmed chemotherapy, then added inotuzumab. Subsequently we added blinatumomab as a consolidation approach and the 10-year follow-up data looked good.'
Jabbour shared a list of seven teams of researchers currently testing frontline blinatumomab and inotuzumab combinations in newly diagnosed ALL in older adults. 'All are reporting promising results compared to historical data,' he said. 'We've made progress and survival of older patients is approaching 50% where historically were at 20% overall survival.'
The next frontier has been to remove chemotherapy altogether, Jabbour said. 'As investigators, we have to make every effort to move into a chemotherapy-free approach for these vulnerable patients.'
This chemotherapy-free approach combining blinatumomab and inotuzumab with TKIs has yielded encouraging results, Jabbour said. 'We know immunotherapies are better than chemotherapy; therefore, it's time to combine them with TKIs,' he said. 'We must prevent central nervous system (CNS) relapses because patients are living longer, and these CNS relapses are what's limiting our progress.'
Jabbour highlighted the TKI ponatinib, noting that his and other groups have shown that the use of ponatinib has increased minimal residual disease (MRD)-negative CRs, as well as significantly increasing event-free survival.
Ongoing trials are evaluating further optimizations, including integrating CAR T-cell therapy. 'We are measuring MRD by next-generation sequencing (NGS) at 10-6. If a patient is NGS MRD-negative, then we maintain the TKI and do not go for transplant,' Jabbour said. 'In patients who are NGS MRD-positive, we are offering them CAR T cells. If they become MRD-negative, we maintain the TKI; otherwise, we go for transplant.'
That means, Jabbour said, that ALL has gone from a disease where transplant was the only way to cure patients to potentially being able to offer CAR T and the promise of finite therapy to these patients. 'We are walking away from chemotherapy because the combination of blinatumomab and a TKI are inducing survival at 4 years of 80%-90%,' he said. 'Moving forward, it's time to integrate immunotherapy fully into the frontline setting, along with bispecific antibody-drug conjugates and CAR T cells.'
Jabbour noted that randomized studies are ongoing, with results expected by 2027. 'I hope we will then have a new standard of care for these patients,' he later told Medscape Medical News .
Jabbour disclosed having relationships with AbbVie, Adaptive Biotechnologies, Amgen, Ascentage Pharma Group, Astellas Pharma, Bristol Myers Squibb, Genentech, Incyte, Pfizer, and Takeda.
