The median age of diagnosis of acute lymphoblastic leukemia (ALL) in the United States is 16 years old, making it mainly a disease of children and adolescents; however, more than 45% of ALL cases are observed in patients older than 20 years, with 20% being 55 or older.¹ The past decades have brought about advancements in treatment outcomes, with long-term disease-free survival (DFS) now achievable for adults with ALL. Nevertheless, traditional therapies, like hematopoietic stem cell transplantation (HSCT) (the first-established immunotherapy), fail for a proportion of patients, and prognosis for relapsed or refractory (R/R) disease remains poor. The rapid emergence of novel, highly active, immunotherapies specifically designed for R/R ALL, several of which are now approved, have given hope for improved efficacy with less toxicity.¹

A review of the available antibody and cellular-based immunotherapies for the treatment of patients with R/R ALL has been published by Erik L. Kimble and Ryan D. Cassaday in Leukemia & Lymphoma¹ and is summarized below.

Monoclonal antibodies

One of the early approaches to antigen-specific immunotherapy was the use of monoclonal antibodies directed at surface antigens, such as CD20, a B-cell lineage marker, expressed in 30–50% of ALL patients.

The addition of the anti-CD20 rituximab to standard chemotherapy, has led to significant improvements in the event-free survival (EFS) of patients with CD20-positive Philadelphia chromosome (Ph)-negative ALL without increasing toxicity. For this reason, rituximab is now frequently added to chemotherapy, although it has not yet gained approval by regulatory agencies in this setting.

Another monoclonal antibody binding to the small extracellular loop of CD20 is ofatumumab, which has demonstrated superior in vitro complement-mediated cytotoxicity compared to rituximab. In a phase II trial evaluating the activity and safety of ofatumumab in combination with hyper-CVAD chemotherapy in patients with Ph-negative CD20-positive B-cell ALL (B-ALL), the combination was found to be safe and effective with an estimated 4-year EFS reaching 59%.

Antibody–drug conjugates

Inotuzumab ozogamicin (InO) is a humanized anti-CD22 IgG4 monoclonal antibody conjugated to calicheamicin, a cytotoxic agent that when activated and intercalated into DNA causes double-strand breaks to induce damage independent of the cell cycle progression. InO has been approved as a monotherapy in the salvage setting for the treatment of R/R B-ALL by the U.S. Food and Drug Administration (FDA). Clinical trials have revealed that:

• 74% of patients treated with InO achieved a complete remission (CR) or CR with incomplete hematologic recovery (CRi), 78.4% of whom had no evidence of minimal residual disease (MRD).
• Patients had improved overall survival (OS) partly due to a higher rate of reaching HSCT compared to salvage chemotherapy alone (41% vs 11%; p < 0.001).
• Patients who were able to undergo HSCT after InO had a 2-year OS post-HSCT equal to 41%.
• The combination of InO with low dose salvage chemotherapy such as mini-hyper-CVAD is achievable and may provide additional survival benefits.
• Initial reports on the combination of InO and bosutinib show promising activity, with a CR/CRi rate of 83% in a modest cohort of 18 patients with R/R Ph-positive B-ALL. Complete molecular response (CMR) rate was 53% in the 15 patients evaluated.
• HSCT after InO is associated with a well-established risk of hepatic sinusoidal obstruction syndrome (SOS) which increases with cumulative cycles of therapy and dual-alkylator conditioning regimens. Due to this, careful consideration should be taken when selecting conditioning regimens and if possible, InO cycles should be limited to two or less.

Several trials are also exploring the extension of InO to the frontline setting:

• The ongoing Alliance A041501 trial is evaluating the addition of InO to the frontline pediatric-inspired regimen of CALGB 10403 in young adults aged 18 to 40 years old with newly diagnosed B-ALL.
• In mature adults, there is accumulating evidence with InO and low-dose chemotherapy combinations. A single-center experience of 52 patients with Ph-negative B-ALL treated with frontline InO and mini-hyper-CVAD reported 100% CR/CRi rates, with 78% of evaluable patients (n = 46) achieving MRD negativity. Early mortality was not observed and after a median follow-up of 29 months, the 2-year median progression-free survival (PFS) and OS were 59% and 66%, respectively.
• The phase II INITIAL-1 trial is assessing the use of InO for induction therapy followed by chemotherapy consolidation and maintenance in older adults with Ph-negative B-ALL. Initial results are encouraging, with all patients achieving a CR/CRi and 17 of 23 patients (74%) achieving MRD negativity.

Bispecific T-cell engagers (BiTEs)

Blinatumomab is the first BiTE antibody developed to redirect the specificity of endogenous T cells in vivo, hence promoting the serial lysis of tumor cells. It is composed of two single-chain variable fragments (scFvs) connected by a flexible linker, imparting specificity for CD3 and CD19. Blinatumomab is metabolized in the bloodstream by protein cleavage without involving renal or hepatic clearance. To prevent infusion reactions, dexamethasone is administered at the beginning of each infusion cycle and for patients with high tumor burden, pre-phase cytoreduction can be given to prevent cytokine release syndrome (CRS).

The phase III TOWER trial compared salvage chemotherapy and blinatumomab in patients with Ph-negative B-ALL:

• Patients randomized to the blinatumomab arm had superior rates of CR (34% vs 16%; p < 0.001), 6-month EFS (4.6 vs 7.3 months, HR: 0.55; p < 0.001), and OS (7.7 vs 4.4 months, HR: 0.71; p = 0.01).
• The rate of MRD-negative responses with blinatumomab was 76% among those in a CR.
• The incidence of neutropenia or infection was lower with blinatumomab than with chemotherapy.
• Grade ≥3 CRS or neurotoxicity occurred in 5% and 10% of the patients who received blinatumomab, respectively.

The single-arm, multicenter ALCANTARA trial assessed the efficacy of blinatumomab as a monotherapy for R/R Ph-positive B-ALL:

• CR rate was 36%, and 88% of these patients had MRD negativity.
• Median relapse-free survival (RFS) was 6.7 months and did not differ based on MRD response.
• Median OS at the end of Cycle 2 was not reached for patients who achieved an MRD-negative response.
• Propensity score analyses suggest a higher rate of CR/CRi (36 vs 25%, OR: 1.70; p = 0.076) and better OS compared to historical patients receiving chemotherapy (HR: 0.77; p = 0.031).

The effects of HSCT after salvage with blinatumomab are not well defined. A post-hoc analysis of the TOWER trial did not show a significant survival benefit from HSCT, indicating that durable responses are possible without subsequent HSCT. In contrast, the phase III AALL1331 trial presented evidence in favor of HSCT post-blinatumomab. Pediatric and adolescent and young adult Ph-negative B-ALL patients in first relapse were randomized to receive chemotherapy or blinatumomab, and then allogeneic HSCT. Patients in the blinatumomab arm had better rates of MRD clearance, OS, and DFS with substantially less toxicity. The survival benefit of blinatumomab may be due to its ability to bridge patients to HSCT compared to the control (73% vs 45%, respectively; p = 0.0001).

The single-arm, phase II BLAST trial evaluated 116 patients who received blinatumomab for MRD (defined as MRD >10⁻³ after at least three blocks of intensive chemotherapy). Based on the results from this trial, blinatumomab became the first agent approved by regulatory authorities for the treatment of MRD in ALL:

• 78% of the patients achieved an MRD-negative response.
• Complete MRD responders (no detectable MRD) had longer RFS (23.6 vs 5.7 months; p = 0.002) and OS (38.9 vs 12.5 months; p = 0.002) compared with MRD-nonresponders.
• Median OS was not reached in patients who achieved a complete MRD response after Cycle 1, in CR1 or received an allogeneic HSCT in continuous CR.

In the frontline setting several trials have explored the use of blinatumomab due to its favorable toxicity profile and ability to eliminate chemo-resistant disease:

• The SWOG 1318 trial is investigating the use of blinatumomab as first-line therapy for adults ≥65 years of age with B-ALL.
  • Blinatumomab followed by POMP (6-mercaptopurine, vincristine, methotrexate, prednisone) maintenance achieved a CR/CRi in 66% of patients with Ph-negative B-ALL (median age: 75 years).
  • MRD data was available for 19 patients and of these, 92% were MRD-negative at the end of Cycle 1.
  • DFS and OS at 1 year were 56% and 65%, respectively.
• The phase II GIMEMA LAL2116 D-ALBA trial evaluated first-line dasatinib and steroids followed by blinatumomab consolidation in adult patients with newly diagnosed Ph-positive ALL.
  • Blinatumomab consolidation was able to clear resistant residual disease associated with the development of ABL kinase domain mutations, leading to a molecular response rate of 81% by the end of the fourth cycle of blinatumomab (CMR rate was 47%).

Checkpoint inhibitors

According to a single center experience with pembrolizumab for the treatment of MRD, checkpoint inhibitors appear to have limited response as a monotherapy. However, they may be more effective as an adjunct or rescue therapy in patients receiving antigen-directed immunotherapy, where T-cell exhaustion may signify treatment failure. Ongoing early trials combining blinatumomab or cellular immunotherapies with immune checkpoint inhibitors have suggested they are safe and effective.

Cellular immunotherapies

Chimeric antigen receptors (CAR) are recombinant antigen receptors consisting of an extracellular antigen-binding domain linked to one or more intracellular T-cell signaling domains, that can lyse target antigen-expressing cells. CAR T-cells targeting CD19, an ideal lineage-defining antigen, were the first to demonstrate significant clinical efficacy in patients with B-ALL with limited ‘on-target off-tumor’ toxicities.

CAR T-cell manufacturing starts with collection of peripheral blood lymphocytes, followed by selection and stimulation of T cells and transduction of the CAR gene. The transduced cells are then expanded in vitro over 2–3 weeks before they are ready for infusion. Prior to infusion, most patients will receive lymphodepletion chemotherapy to create a favorable host immune environment that will encourage CAR T-cell expansion, function, persistence, and better clinical outcomes.

The design, product formulation, dose, and administration procedures vary across centers, limiting clinical comparisons. In aggregate, the experience with CD19 CAR T-cell therapy highlights the following:

• Vigorous activity in the R/R setting with high rates of CR (69–85%).
• Near-universal MRD clearance among responders.
• CD19 dim/negative subsets do not appear to prevent response to CD19 CAR T-cells, although there may be a higher rate of failure in patients previously treated with blinatumomab.
• Despite encouraging efficacy, responses appear to be less durable compared to the clinical experience with CD19 CAR T-cells for aggressive non-Hodgkin lymphomas.

The second-generation CD19-directed tisagenlecleucel (CTL019), is the first commercially available CAR T-cell product for the treatment of B-ALL for patients up to 25 years old with refractory disease or in second or greater relapse. Brexu-cel, formerly KTE-X19,  was recently approved for the treatment of adult patients with ALL based on results from the phase II multicenter ZUMA 3 trial, which found that:

• Over 70% of treated patients were able to achieve CR/CRi, 97% of which were MRD- negative.
• The median duration of these responses was 12.8 months, with less than one-fifth of subjects receiving subsequent allogeneic HSCT.

Despite its positive outcomes CAR T-cell therapy can also cause antigen-dependent toxicities such as CRS and neurotoxicity. Both toxicities are mostly reversible, although fatalities do occur. CRS usually presents in the first 14 days after CAR T-cell infusion and it is characterized by fever, constitutional symptoms, hypotension, capillary leak, organ dysfunction, and coagulopathy. Neurotoxicity, also known as immune effector cell-associated neurotoxicity syndrome (ICANS), is distinguished by dysgraphia, delirium, speech disturbances, focal neurological deficits, seizures, and occasionally coma. It can present together with the onset of CRS, but it may also occur later. The incidences of CRS and neurotoxicity can be influenced by tumor burden, lymphodepletion, T-cell dose, and the specific CAR construct (see Table 1 and Table 2 for preventative interventions). Other toxicities include infectious complications of CD19 CAR T-cells, persistent cytopenias, macrophage activation syndrome, and cardiovascular events.

Table 1. Early interventions to prevent severe CRS/ICANS after CD19 CAR T-cell therapy for ALL*

Table 2. CRS and ICANS prophylactic strategies under investigation*

Most patients who receive CAR T-cell therapy for ALL will eventually have an antigen-positive or antigen-negative relapse. Antigen-positive relapse usually occurs within 1 year after CAR T-cell infusion when the resistant leukemic blasts retain the target-antigen phenotype. This is due to limited CAR T-cell surveillance, heralded by loss of B-cell aplasia in patients treated with CD19 CAR T-cells. Optimized strategies to overcome the loss of CAR function are lymphodepleting regimens, fully human CAR constructs, sequential CAR T-cell infusions, and alternative cellular engineering methods. Antigen-negative relapse occurs in 30% of adults with B-ALL who relapse soon after CD19 CAR T-cell infusion due to the loss or modulation of target-antigen expression in a fraction of tumor cells. In this setting, alternative-antigen targeting of CD22 or BAFF-R appears to be yielding favorable results.

To mitigate the risk of relapse after CD19 CAR T-cells, consolidation with allogeneic HSCT can be used. Research has demonstrated that it is not associated with increased risk of graft-versus-host disease (GvHD) or nonrelapse mortality (NRM), and that it eliminates residual CAR T-cells and enhances anti-leukemia efficacy.

Approach to sequencing of immunotherapy in adults with R/R B-ALL

When sequencing immunotherapy for patients with R/R B-ALL the initial treatment response is an important consideration as well as the ability to maintain that response. Table 3 summarizes the optimal conditions under which different immunotherapy agents may be used in this patient population, while taking into consideration logistical and social issues. HSCT is usually recommended following response to all these therapies in the salvage setting.

Table 3. Evidence-based opinions on optimal utilization of immunotherapy agents for adult B-ALL*

Blinatumomab and CD19 CAR T-cells may achieve durable remissions without allogeneic HSCT in a subset of patients with excellent responses to them, whereas such outcomes are rarely seen following therapy with InO. Therefore, if consolidative allogeneic HSCT is in doubt, CD19- directed therapies may be chosen.

Summary

Overall, this review provides a clinical and biologic framework to support treatment choices for adults with ALL. Antigen-specific immunotherapies for B-ALL have demonstrated remarkable clinical efficacy and are rapidly advancing. Future efforts should focus on integrating these agents into earlier phases of treatment.