Reduced chemotherapy and chemotherapy-free regimens for patients with ALL

Limitations of chemotherapy in the treatment of ALL

Traditionally, chemotherapy has played an integral role in the treatment of acute lymphoblastic leukemia (ALL), and is key in induction, consolidation, and maintenance regimens.^1,2 However, it has a number of limitations. As it is a non-selective cytotoxic therapy, it does not specifically act on cancer cells and a number of adverse events (AEs) can result from its effect on healthy cells, such as nephrotoxicity, hepatotoxicity, neurotoxicity, cardiotoxicity, and hematologic toxicities.³ This off-target DNA damage in healthy tissues can also lead to accelerated cellular aging.³ 

Older patients are generally less able to tolerate chemotherapy than younger patients, likely due to reduced drug clearance and smaller volumes of drug distribution.³ These differences may result from poorer liver and kidney function, and lower total body water percentages.³ The prolonged organ toxicity, immunosuppression, and amplification of chronic diseases that accompany chemotherapy impact quality of life, particularly in elderly patients who are less able to care for themselves.⁴ 

Following chemotherapy treatment, remaining cancer cells (measurable residual disease [MRD]) adopt slow cycling, causing reduced susceptibility to conventional chemotherapy and subsequent disease persistence.⁵ Achievement of MRD-negativity is associated with better survival outcomes in patients with cancer, supporting investigation into therapeutics that either target MRD cells or prevent MRD occurrence.⁵ Given these limitations, there has been a shift towards investigating strategies that would reduce reliance on chemotherapy-based treatment options to improve patient tolerance, reduce systemic AEs, and reduce risk of MRD cycling.^1,5,6

Immune-based therapeutic strategies in reduced chemotherapy and chemotherapy-free ALL regimens

Immunotherapies, such as bispecific T-cell engagers (BiTEs), antibody–drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies, utilize the body’s own immune system to recognize and attack cancer cells.⁶ A number of immunotherapies are currently indicated as monotherapies for the treatment of relapsed/refractory (R/R) ALL (Table 1). More recently, immunotherapies are being investigated in combination with chemotherapy or tyrosine kinase inhibitors (TKIs) as first-line treatment for ALL.¹

Table 1. Immunotherapies approved as monotherapy for the treatment of ALL

ALL, acute lymphoblastic leukemia; allo-HSCT, allogeneic hematopoietic stem cell transplantation; B-ALL, B-cell ALL; BCP, B-cell precursor; brexu-cel, brexucabtagene autoleucel; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; InO, inotuzumab ozogamicin; MRD, measurable residual disease; ND, newly diagnosed; Ph, Philadelphia chromosome; R/R, relapsed/refractory; TKI, tyrosine kinase inhibitor.

BiTEs

BiTEs comprise of two arms that bind to T cells and tumor cells, triggering T-cell activation and subsequent selective cytotoxicity (Figure 1).¹⁵ 

Blinatumomab is approved as a monotherapy by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of specific ALL subtypes (Table 1), and has become a key therapeutic option for patients with R/R disease following positive findings from the MT103-211 (NCT01466179), TOWER (NCT02013167), and ALCANTARA (NCT02000427) trials.^7,8,17 It is recommended over chemotherapy for the treatment of adolescent and young adult patients with R/R B-cell ALL (B-ALL) by the American Society of Hematology.¹⁸ The use of blinatumomab in combination with chemotherapy or other targeted therapies is currently being assessed in clinical trials, largely focusing on consolidation or maintenance therapy; however, more recently, evidence has suggested that blinatumomab may be effective when integrated into first-line regimens for newly diagnosed (ND) ALL.¹

In the ongoing phase III ECOG-ACRIN-E1910 trial (NCT02003222) in patients with ND B-ALL, at a median follow-up of 43 months, an overall survival (OS) benefit was demonstrated at 3 years in patients who received blinatumomab + chemotherapy vs chemotherapy alone (85% vs 68%; p = 0.002).¹⁹ Grade 3 non-hematologic AEs occurred at similar rates between treatment arms (43% vs 36%); however, Grade ≥3 treatment-related neurologic events were more common with blinatumomab + chemotherapy vs chemotherapy alone (23% vs 5%; p < 0.001).¹⁹

The combination of blinatumomab + chemotherapy is also being investigated in the ongoing phase III AALL1731 trial (NCT03914625) in adults and in pediatric patients aged ≥1 and <10 years with B-ALL. Results from the pediatric cohort of this study showed that 3-year disease-free survival (DFS) was greater in patients who received blinatumomab + chemotherapy vs chemotherapy alone (96.0% vs 87.9%; p = 0.00004).²⁰ During blinatumomab cycles, the incidence of Grade ≥3 blinatumomab-associated toxicities, such as cytokine release syndrome (CRS; 0.2%), sepsis and catheter related infections (2.9%), or seizures (0.8%), was low.²⁰

The phase II GIMEMA LAL2317 trial (NCT03367299), evaluating the impact of sequential chemotherapy and blinatumomab on MRD response and survival in patients with ND Philadelphia chromosome-negative (Ph−) B-cell precursor ALL (BCP-ALL), showed that 93% of patients achieved MRD negativity after the first cycle of blinatumomab.²¹ Stratification by age revealed improved complete response (CR; 94%, 92%, and 64% for 18–40, 40–55, and >55 year olds, respectively; p < 0.001) and OS (76%, 74%, and 49%, respectively; p = 0.00013) in younger vs older patients.²¹

Across the ECOG-ACRIN-E1910, AALL1731, and GIMEMA LAL2317 trials, blinatumomab demonstrated efficacy and tolerability in adult and pediatric patients with ND B-ALL and BCP-ALL, supporting its use outside of the R/R setting. 

ADCs

ADCs are synthetic molecules that target antigens expressed exclusively on tumor cells or are overexpressed during carcinogenesis (Figure 2).²² Inotuzumab ozogamicin (InO) is an FDA- and EMA-approved humanized immunoglobulin G4 anti-CD22 antibody that is indicated for the treatment of adult and pediatric patients with R/R BCP-ALL (Table 1).^9,10 Research into InO has mostly been in the R/R setting, but more recent studies have expanded into first-line combinations with chemotherapy and/or other immunotherapies.²³

In the phase III INO-VATE study (NCT01564784), comparison of InO with chemotherapy in adult patients with R/R CD22+ B-ALL found higher CR rates (80.7% vs 29.4%; p < 0.001), MRD negativity rates (78.4% vs 28.1%; p < 0.001), and median OS (7.7 months vs 6.7 months; p = 0.04).²⁴ Grade ≥3 AEs occurred in 46% of patients receiving InO and 43% of patients receiving chemotherapy.²⁴ Hepatic AEs of any grade, such as veno-occlusive disease (VOD; 11% vs 1%), were more common in patients receiving InO vs chemotherapy.²⁴

In a phase I/II study (NCT01371630), the addition of blinatumomab to InO + dose-reduced hyper-fractionated cyclophosphamide, vincristine, and dexamethasone alternating with dose-reduced methotrexate and cytarabine chemotherapy in patients with R/R, Ph− B-ALL, gave an overall response rate of 80%, a CR rate of 57% and a best MRD negativity rate of 81%, similar to rates without blinatumomab.²⁵ Common AEs included prolonged thrombocytopenia (76%), infection (53%), and nausea (35%). Hepatic AEs were reported in 33% of patients, including VOD in 10% of patients.²⁵

Several studies investigating InO combination therapies in the first-line setting are underway, largely focusing on older adult patients.²³ In the ongoing Alliance A041703 study (NCT03739814), InO followed by blinatumomab is being evaluated in patients aged ≥60 years with ND Ph− B-ALL, with results from cohort 1 demonstrating an 85% composite CR rate after two cycles of InO and 97% following two cycles of blinatumomab.²⁶ At 1 year, the event-free survival rate was 85% and the OS rate was 75%.²⁵ Long-term follow-up of this study is warranted to confirm durability of responses.²³

Results from these studies indicate that InO, alone or in combination with chemotherapy or immunotherapies, is a viable treatment option for patients with CD22+ B-ALL across age groups.

CAR T-cell therapies 

CAR T-cell products are genetically engineered to include fusion proteins that guide them towards molecular markers on tumor cell surfaces, enabling selective targeting of cancer cells (Figure 3).²⁷ Brexucabtagene autoleucel (brexu-cel) is a CAR T-cell therapy approved by the FDA and EMA for the treatment of adult patients with R/R BCP-ALL (Table 1).^11,12 Tisagenlecleucel is the only FDA- and EMA-approved CAR T-cell therapy for the treatment of pediatric patients with ALL (Table 1).^13,14 Although only currently indicated for R/R disease, integration of CAR T-cell therapies into first-line treatment in concomitant or sequential regimens is of interest to potentially increase cure rates and reduce the need for chemotherapy.²⁷

In the phase I/II ZUMA-3 trial (NCT02614066), evaluating the efficacy and safety of brexu-cel in adult patients with R/R BCP-ALL, at 3 years, the median CR rate was 63%, duration of response was 14.6 months, and OS was 25.6 months in the overall population and 38.9 months in responders.²⁹ At 5 years, the OS rate was 40%, with a median OS of 25.6 months in the overall population and 53.5 months in responders.³⁰ The most common Grade ≥3 AEs were anemia and pyrexia.^29–31 

In a retrospective study by the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) consortium, which was formed to study brexu-cel in patients with R/R B-ALL as a standard-of-care therapy, 90% of 168 efficacy-evaluable patients achieved a CR/CR with incomplete hematologic recovery, and 79% an MRD− CR.³² At a median follow-up of 11.4 months, 6- and 12-month progression-free survival (PFS) rates were 59% and 48%, respectively; CRS was reported in 84% of patients and immune effector cell-associated neurotoxicity syndrome in 56%.³²

These studies support CAR T-cell therapy as a therapeutic option for the treatment of patients with R/R B-ALL; however, further research into its use in other ALL lineages and younger patient populations is warranted to expand usage.

Immunotherapies in combination with TKIs

Combination therapies of TKIs with chemotherapy are routinely used in first-line regimens for Ph+ ALL,² and are now being investigated in combination with immunotherapies.³³ They act by blocking tyrosine kinase and other intracellular kinases in order to regulate cell growth and angiogenesis, preventing disease progression. However, those that inhibit multiple kinases, in particular, have an increased risk of toxicities, and management of these toxicities is crucial to prevent long-term sequelae.³⁴

A study of the efficacy and safety of blinatumomab + a TKI vs chemotherapy + a TKI in patients with de novo or relapsed Ph+ B-ALL found that rates of OS, PFS, and non-relapse mortality (NRM) were similar between treatment groups (2-year OS, 87% vs 78%; PFS, 81% vs 54%; NRM, 6.3% vs 14%), although NRM was numerically higher with chemotherapy.³³ Severe treatment-related AEs were more common in patients receiving chemotherapy vs blinatumomab, suggesting blinatumomab + TKIs could be an effective and tolerable chemotherapy-free approach to treating this patient population.³³

Implementing reduced chemotherapy and chemotherapy-free regimens into clinical practice

Deciding which reduced chemotherapy or chemotherapy-free regimen is most appropriate for each patient requires multifactorial consideration, with aspects such as age, ALL subtype, and treatment availability playing key roles.^1,4

Elderly patients

Therapy selection for older or frail patients can be challenging due to more frequent adverse prognostic features and comorbidities, and risks associated with treatment such as organ damage, immunosuppression, and exacerbation of underlying conditions.⁴ While blinatumomab has been shown to be effective in elderly patients and does not pose the same risk of myelosuppression as conventional chemotherapy, CAR T-cell products, or ADCs, further randomized comparative studies of blinatumomab vs chemotherapy and other combinations are warranted to confirm safety and tolerability.^2,4,35 At present, blinatumomab with a TKI is considered to be a tolerable treatment option that provides durable remissions in elderly patients with ALL, eliminating the risk of chemotherapy-associated AEs.⁴ Furthermore, InO is efficacious and tolerable in older patients with ND B-ALL, with improved response and survival rates over chemotherapy, suggesting that integration into first-line regimens may be a viable for this population.³⁶ In addition, brexu-cel may offer another chemotherapy-free option in this population.⁴ 

Pediatric patients

Pediatric patients with ALL are usually treated according to risk, identified through bone marrow or peripheral blood testing for genetic abnormalities, which determines the intensity of therapy required.³⁷ While they are generally able to tolerate chemotherapy better than adult patients,³ reducing chemotherapy through the introduction of immunotherapies has been of great clinical interest given the potential to improve outcomes.³⁸ Blinatumomab has shown efficacy and tolerability in pediatric patients with SR B-ALL,²⁰ leading to its approval by the FDA and EMA for patients aged ≥1 month (Table 1).^7,8 Similarly, InO has demonstrated encouraging efficacy and safety results in younger patients with Ph− B-ALL,²³ and is approved by the FDA for pediatric patients aged ≥1 year with BCP-ALL (Table 1).⁹ While studies evaluating brexu-cel and other CAR T-cell therapies in pediatric patients with ALL are ongoing,³⁸ tisagenlecleucel is the only CAR T-cell therapy available in this population (Table 1).^13,14 

Ongoing unmet needs and future directions

Use of response-based factors, such as MRD, to guide ALL treatment have been of particular interest in recent years.³⁹ Integration of immunotherapies into ALL treatment regimens may help address the challenge of remaining MRD following traditional chemotherapy.¹ A meta-analysis, assessing the prognostic impact of MRD in ALL, found that 10-year DFS in patients who achieved MRD negativity was 64% vs 21% in those who were MRD+ after induction and/or consolidation therapy.³⁹ Factors such as MRD assay sensitivity/specificity, timing of assessment, and disease-related features may affect the prognostic significance of assessment, warranting further studies into MRD-guided therapy.³⁹ 

There are some access barriers to immunotherapies, such as lack of familiarity with guidelines, healthcare infrastructure, and socioeconomic background.⁴⁰ These barriers are often amplified in specific populations such as racial/ethnic minorities and elderly patients, impacting outcomes and patient experience.⁴⁰ However, outpatient administration of blinatumomab to pediatric patients has shown improvements in symptom burden and quality of life for both patients and caregivers,⁴¹ and outpatient administration of brexu-cel in patients with B-ALL and mantle cell lymphoma demonstrated similar efficacy to inpatient delivery, with no increase in NRM or toxicities.⁴² These studies suggest that at-home or outpatient delivery of immunotherapies to treat ALL is a feasible option and should be explored further to improve patient experience.

Conclusion

While chemotherapy remains central to ALL treatment,² broad cytotoxicity, poor tolerability in older patients, and MRD persistence provide compelling rationale for reducing or eliminating its use.^3,5 Integration of immunotherapies, such as BiTEs, ADCs, and CAR T-cell therapies, as monotherapies or in combination with chemotherapy or TKIs, offers a significant step towards improved outcomes for patients across age groups and disease subtypes.¹ Continued investigation through clinical trials, long-term follow-up studies, and real-world evidence will be essential to refine treatment algorithms, address ongoing unmet needs, and ultimately deliver effective, tolerable therapies to patients with ALL.

This educational resource is independently supported by Amgen. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.