What is the potential impact of integrating reduced-chemo and chemo-free approaches into ALL treatment strategies?

The ALL Hub was pleased to speak with Elias Jabbour, MD Anderson Cancer Center, Houston, US. We asked, What is the potential impact of integrating reduced-chemotherapy and chemotherapy-free approaches into acute lymphoblastic leukemia (ALL) treatment strategies? 

In this interview, Jabbour discusses the growing evidence for chemotherapy-reduced and chemotherapy-free approaches in ALL. He highlights how advances in targeted therapies, including blinatumomab, inotuzumab ozogamicin (InO), tyrosine kinase inhibitors (TKIs), and chimeric antigen receptor (CAR) T-cell therapy, alongside measurable residual disease (MRD)-guided strategies, are changing the management of ALL. He also explores the potential to reduce chemotherapy intensity, limit the need for allogeneic hematopoietic stem cell transplantation (allo-HSCT), and improve long-term outcomes of ALL, across subtypes and patient populations.  

Key points 

• Limiting exposure to intensive chemotherapy and its associated toxicity is an important consideration driving the development of chemotherapy-reduced and chemotherapy-free treatment strategies in ALL. Targeted therapies, including blinatumomab, InO, TKIs and CAR T-cell therapy, together with improved MRD assessment, are providing opportunities to reduce chemotherapy exposure while maintaining disease control.^1–5 
• Clinical evidence supporting chemotherapy-reduced and chemotherapy-free treatment strategies in ALL is accumulating, with studies across multiple patient populations demonstrating that integrating immunotherapies and other targeted therapies can improve outcomes while reducing reliance on intensive chemotherapy.^1–5 
• In the phase III ECOG-ACRIN E1910 trial (NCT02003222) in adults with newly diagnosed (ND) Ph−, MRD-negative B-ALL (n = 224), adding 2 cycles of blinatumomab to consolidation chemotherapy improved overall survival (OS; at 3 years, 85% vs 68%; p = 0.002) and improved relapse-free survival (80% vs 64%) vs chemotherapy alone.¹ 
• Long-term follow-up (median, 4.5 years) from a phase II study (NCT02877303) in young adults with ND B-cell ALL (N = 75) showed the addition of InO to hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and sequential blinatumomab was associated with improved survival and durable remissions, including 94% MRD negativity by flow cytometry.² The 4-year OS and event-free survival (EFS) rates were 100% and 91%, respectively.² 
• Reduced-chemotherapy approaches have also demonstrated promising outcomes in older adults. In Cohort 1 (n = 33) of the ongoing Alliance A041703 study (NCT03739814), chemotherapy-free treatment with InO followed by blinatumomab achieved a composite complete remission rate of 97% in older adults (≥60 years) with ND Ph−, CD22-positive B-cell ALL.³ At a median follow-up of 30 months, the 1-year EFS and OS rates were 75% and 85%, respectively.³ 
• The phase III GOLDEN GATE study (NCT04994717) is evaluating blinatumomab alternating with low-intensity chemotherapy in adults with ND Ph− B-ALL to determine whether chemotherapy can be reduced without compromising efficacy.⁴ 
• Chemotherapy-free approaches have demonstrated promising efficacy in Ph+ ALL. In a propensity score analysis of adults with newly diagnosed Ph+ ALL, treatment with blinatumomab + ponatinib was associated with improved PFS and OS compared with hyper-CVAD + ponatinib, while reducing the need for allogeneic stem cell transplantation and non-relapse mortality (NRM).⁵ The analysis included 40 propensity score-matched patients per treatment group from two prospective phase II studies (NCT01424982 and NCT03263572).⁵ 
• Patient selection remains essential when considering reduced-chemotherapy or chemotherapy-free approaches.⁶ MRD-guided treatment is an integral component of routine ALL management and informs risk-adapted treatment decisions, helping identify patients who may benefit from reduced treatment intensity.⁷  
• Current and ongoing research is exploring how immunotherapies can be incorporated in earlier lines of treatment to enable chemotherapy reduction, with the potential to decrease toxicity, reduce reliance on allogeneic stem cell transplantation, shorten treatment duration, and improve long-term outcomes.⁷ 

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