Chemotherapy-Free Regimens Gain Ground in Older Patients With ALL

Over the past decade, there have been exciting advancements in the treatment of B-cell acute lymphoblastic leukemia (B-ALL); however, the treatment of older adults remains a challenge. Historically, older adults treated with conventional chemotherapy had dismal outcomes, with an overall survival (OS) of approximately 20% at 5 years.^1,2 Poor tolerance of chemotherapy with high rates of treatment-related complications and death, as well as unfavorable disease biology leading to more resistance and relapse, explains most of the relatively poor survival outcomes.^1,3-5

Incorporating highly effective and less toxic targeted agents has improved survival for older adults with B-ALL to 50% or more in clinical trials.^5,6 The most notable drugs are blinatumomab (Blincyto), inotuzumab ozogamicin (InO; Besponsa), and BCR::ABL1-selective tyrosine kinase inhibitors (TKIs).

Recent advancements and future directions in the treatment of older adults with B-ALL, with a focus on novel combination regimens in the frontline setting, were discussed during the Society of Hematologic Oncology (SOHO) 2024 Annual Meeting, September 4 to 7, 2024.

Combination Regimens

In Philadelphia chromosome–positive (Ph+) B-ALL, combining BCR::ABL1-selective TKIs with conventional chemotherapy has improved survival for all patients.^7-9 However, with the first- and second-generation TKIs, relapse was common due to BCR::ABL1 kinase domain (KD) mutations and optimal outcomes still required myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT).^8,10,11

Yet for the older adult population who have the highest incidence of Ph+ ALL, this approach remained too toxic, leading investigators to further reduce and eliminate chemotherapy altogether (TABLE 1). The GIMEMA LAL2116 D-ALBA study (NCT027442768) of dasatinib (Sprycel)/corticosteroid induction and dasatinib/blinatumomab consolidation with investigator’s choice postconsolidation therapy in all adults resulted in an OS and event-free survival (EFS) of 80.7% and 74.6%, respectively, at a median follow-up of 53 months^.12

SWOG-1318 study

Similar promising outcomes were reported from the US Intergroup SWOG-1318 study (NCT02143414) of dasatinib/prednisone induction followed by dasatinib/blinatumomab and then dasatinib maintenance in older patients (median age, 73 years) without the added toxicities of chemotherapy or transplant.¹³

With the use of ponatinib, a third-generation TKI that overcomes resistance by BCR::ABL1 KD mutations including T315I, the goal of decreasing the risk of relapse further and reducing the need for intensive treatment approaches including alloHSCT was possible.⁹ Ponatinib (Iclusig) plus blinatumomab produced excellent responses (complete molecular response, 87%), with a 2-year EFS of 80% and an OS of 90%.¹⁴

Additionally, these systemic chemotherapy-free regimens resulted in lower rates of treatment- related and nonrelapse related mortality (NRM). Dual TKI inhibition for Ph+ B-ALL is also being studied in the phase 1 trial (NCT03595917) combining dasatinib and asciminib (Scemblix) with prednisone.¹⁵ Long-term follow-up is needed to confirm the durability of these regimens, especially as isolated central nervous system (CNS) relapses are seen and remain a concern.

Chemotherapy-Free Regimens

The introduction of chemotherapy-free regimens in Ph+ disease paved the way for the approach in Ph-negative B-ALL. Given the impressive activity of both blinatumomab and InO in the relapsed/refractory setting, these drugs quickly entered studies in the frontline setting, including for older adults (TABLE 2).^16-19 Blinatumomab is safe and relatively well tolerated in older patients.

However, as demonstrated in SWOG-1318, blinatumomab alone, followed by maintenance chemotherapy, yields a relatively low complete response (CR) rate (66%), with a high relapse rate and 3-year OS of only 37%.²⁰

Subsequent trials, most notably ECOGACRIN E1910 (NCT02003222), established the benefit of adding blinatumomab to consolidation in the measurable residual disease (MRD)–negative setting or as treatment of persistent or recurrent MRD, highlighting its effectiveness when treating lower disease burden.^21-24 Unfortunately, these trials also demonstrated that older adults still experience toxicities despite dose reductions and elimination of certain chemotherapy agents, and a survival benefit possibly limited to adults 55 years and older.^21-24

Unlike blinatumomab, InO appears effective irrespective of disease burden and has been a promising addition as induction therapy for B-ALL with or without chemotherapy.^21,25-27 Investigators the combination of InO with mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine. Because of increased risk of toxicity and deaths during remission, the regimen was amended to include dose reductions and the addition of blinatumomab.

Despite these changes, there was limited impact on survival for older adults, as the median OS was 46.6 months in patients 65 to 69 years and 34.7 months in patients 70 years or older, with an NRM of 40.5% at 5 years for all patients.^21,28

In addition, the EWALL-INO trial (NCT03249870) combined fractionated InO with less-intensive chemotherapy in older adults and produced an overall CR of 88.5% (56.6% MRD negative); however, OS at 1-year was only 66% in patients 66 years and older.²⁵

In the phase 2 GMALL INITIAL-1 trial (NCT03460522), InO induction followed by reduced-intensity chemotherapy resulted in an overall CR rate of 100% (74% MRD negative), with a 3-year OS rate of 73% and an NRM rate of 17%.26

Despite better disease control, this combination may be too toxic for most older patients, leading to high rates of NRM and poor survival.

Secondary Neoplasms

Additionally, high rates of secondary myeloid neoplasms have been reported with the use of InO and chemotherapy.^21,28 A phase 2 study (NCT03739814) aimed to limit toxicity and NRM while remaining highly active in older adults with newly diagnosed Ph-negative B-ALL by giving InO induction followed by blinatumomab consolidation without maintenance therapy.

The composite CR rate was 96%, with a 1-year EFS rate of 75% and 1-year OS rate of 84%.²⁷ There were 9 relapses (2 with concomitant systemic and CNS disease; 4 with CD19 antigen–negative relapse) and 2 deaths in remission reported.²⁷

Long-term follow-up is needed to determine the durability and potential late toxicity of this promising regimen. Additional investigations include combining less-intensive regimens with other targeted agents, such as BCL2/BCL-XL and menin inhibitors.

The use of chemotherapy-free regimens for older adults with newly diagnosed B-ALL has led to substantial improvements in outcomes, offering the opportunity to minimize NRM while maintaining efficacy.

However, the optimal approach for CNS prophylaxis and mechanisms of resistance remains unclear. Therefore, it will be critical to determine the best combination and sequence of these agents. Further evaluation is needed on the role for chimeric antigen receptor T-cell therapy, reduced intensity alloHSCT, and maintenance therapy.

These chemotherapy-free regimens will set a new standard of care for our older adult population with ALL, on which to further optimize through clinical trials.

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