The current treatment landscape of acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a rare hematological disorder with a bimodal incidence in childhood and in older adults. The advent of multiple chemotherapies has drastically improved the survival outcomes in pediatric cases, with a 98% cure rate. However, treatment options for adult patients or those with relapsed or refractory (R/R) disease were limited and had poor outcomes, until recently when novel agents were introduced into the treatment landscape of this patient population. Alexander Gavralidis and Andrew Brunner published a review in Current Hematologic Malignancy Reports on emerging novel treatments that have recently been approved for ALL and describe new diagnostic tools that have advanced treatments.¹

Classifications and diagnosis

The World Health Organization (WHO) classification of ALL is based on cell lineage and recurrent cytogenetic and molecular features, which was expanded in 2016 to include

• B-ALL with an intrachromosomal amplification of chromosome 21:
  • iAMP21
• B-ALL with translocations:
  • BCR-ABL1–like or Philadelphia chromosome (Ph)-like

MRD monitoring

Measurable residual disease (MRD) monitoring is the detection of residual disease after treatment, and MRD negativity has been adopted as a therapeutic endpoint. Flow cytometry, next-generation sequencing (NGS), and other molecular diagnostics tools are used to identify and track lymphoblast populations. Flow assessments of MRD are widely used but are yet to be standardized and vary significantly across centers. NGS assessments may be better suited for capturing subclonal dynamics. MRD detection is used to guide treatment as patients with detectable residual disease may benefit from treatment intensification, while those with deep remissions may be managed with a reduced intensity treatment.

NGS and fluorescence in situ hybridization are tools used to identify kinase translocations that characterize Ph-like B-ALL, such as BCR-ABL1.  

Flow cytometry or immunohistochemistry can be used to identify the expression of lineage-defining antigens, including CD3, CD79a, CD19, and CD10, and can also inform treatment decisions by identifying the presence or absence of cell surface targets, i.e., toward CD19 for blinatumomab therapy, CD20 for rituximab therapy, or CD22 for inotuzumab ozogamicin therapy.

New therapies for ALL

Targeting the Philadelphia chromosome (BCR-ABL1) in ALL

The BCR-ABL1 translocation of t(9;22) (q34.1;q11.2) activates the ABL kinase and results in cellular proliferation. This fusion chromosome was originally the defining mutation in chronic myeloid leukemia and was subsequently found to be present in a subset of patients with ALL. BCR-ABL1 translocation in ALL is more frequent in older adults: it is found in 50% of adults over 50 years old and in 1–5% in children with ALL. Historically, patients with ALL with BCR-ABL1 translocation had poor outcomes, with a 1-year median overall survival (OS) with chemotherapy, but the discovery of tyrosine kinase inhibitors (TKI) has drastically improved outcomes. Imatinib was the first TKI to be developed, followed by dasatinib, nilotinib, ponatinib, and bosutinib.

Imatinib

Imatinib, combined with steroids, is able to induce a high response rate, with a tolerable safety profile in older patients who would otherwise be high risk or ineligible for chemotherapy treatment. However, imatinib is associated with treatment resistance due to relapse with mutational subclones. Y253H is a mutation that is specific to imatinib; new generation TKIs are being researched to target this mutation.

Dasatinib

Dasatinib is a second-generation TKI that is more potent at targeting BCR-ABL1 than imatinib. Dasatinib can also penetrate the blood–brain barrier, which can be an important site for leukemic cell survival. Dasatinib with steroids results in high remission rates, including molecular remissions, with a good safety profile and few treatment-related deaths.   

Patients treated with either dasatinib or imatinib who relapse normally do so due to the presence of T315I resistance mutation. Ponatinib, another TKI, can effectively target Ph+ ALL harboring the T315I mutation, and is an option for second-line treatment (NCT01641107). However, toxicity remains a concern, particularly in terms of vascular events.    

The combination of TKIs and steroids may be able to induce high remission rates, but they do not seem to achieve molecular clearance, and there is concern regarding resistance and relapse. To overcome this, the combination of TKIs with cytotoxic regimens has become more common, particularly in the treatment of younger patients, as it is able to produce favorable responses. This has opened new areas of discussion regarding the optimal therapy for these patients, including whether a chemotherapy backbone is better in the long term, and whether transplant is always necessary.

BCR-ABL1-like (Ph-like) ALL

A subgroup of patients with ALL do not have the BCR-ABL1 fusion gene but exhibit a similar gene expression pattern as patients with Ph+ ALL; these patients are referred to as having Ph-like ALL. Profiling of gene expression patterns have identified actionable kinase alterations, including CRLF2 rearrangements and JAK2 mutations, and the ABL1/ABL2 translocations, however these tests are not readily available outside of research centers. Diagnostic tools to characterize gene expression profiles and identify relevant treatments are being studied.

Blinatumomab

Blinatumomab is an anti-CD3/CD19 bispecific antibody that was approved in the European Union in 2014 and by the U.S. Food and Drug administration (FDA) in 2015 for the treatment of R/R B-ALL. The ALCANTARA (NCT02000427) trial examined the efficacy of blinatumomab in patients with R/R Ph+ B-ALL that failed prior TKI-based therapy. The reported complete remission (CR)/CR with partial hematologic recovery (CRh) rate was 36%. Among these, 88% were MRD negative. In another study (NCT01466179) of Ph-negative B-ALL, blinatumomab was found to achieve a CR in 33% of patients. Following on from these studies, a phase III study was undertaken comparing blinatumomab with standard-of-care chemotherapy regimens (NCT02013167) and reported CR/CRh/partial remission rate of 44% vs 25% (p < 0.001), respectively, and the OS was 7.7 months vs 4.0 months (p = 0.01), respectively. Further work (NCT01207388) has also found that it may be useful in treating MRD following initial chemotherapy, with 78% of patients achieving MRD negativity after treatment. Blinatumomab is currently being assessed in frontline and posttransplant maintenance settings.

Inotuzumab ozogamicin

The antibody–drug conjugate, inotuzumab ozogamicin, is an anti-CD22 antibody that is attached to calicheamicin. The phase III INO-VATE ALL study (NCT01564784) comparing inotuzumab ozogamicin with the standard salvage therapy reported increased overall response in patients treated with inotuzumab ozogamicin (CR, 81.0% vs 29.4%; p < 0.001). The OS was prolonged to 7.7 months in the treatment group vs 6.7 months in the control group (p = 0.04), and more patients treated with inotuzumab ozogamicin were able to proceed to transplant. In another phase II study (NCT01371630), the addition of inotuzumab to low-intensity cyclophosphamide, vincristine, doxorubicin, and dexamethasone was able to achieve high responses, with 78% responding to treatment, 59% obtaining a CR, and 82% achieving MRD negativity. Veno-occlusive disease was the main safety issue in patients treated with inotuzumab ozogamicin.  

Chimeric antigen receptor T cells (CAR T-cell therapy)

On August 30, 2017, the FDA approved tisagenlecleucel, a CD19-directed CAR T-cell product, for the treatment of patients with R/R B-ALL aged ≤ 25. This was based on the results from the pivotal multicenter ELIANA (NCT02435849) study, with a CR/CRi rate of 83%. The approval was not extended to older patients because of excess neurotoxicity. Early data indicate that CAR T-cell therapy could be effective in R/R B-ALL, with approximately 90% remission rates. Data from longer follow-ups show that the younger population had favorable survival outcomes, particularly in patients with lower disease burden the time of CAR T-cell infusion. A safety concern with CAR T-cell therapy is cytokine release syndrome and neurotoxicity.

Conclusion

The treatment landscape of ALL has changed significantly in the last 5 years. Many new therapies have been approved in the R/R setting and are being evaluated in other settings. MRD assessments have become crucial in monitoring disease response and guiding treatment. However, there is a great need for novel therapies, in particular for T cell ALL in the R/R setting, and a better understanding of resistance and relapse after CAR T-cell therapy failure.