Optimizing the treatment of acute lymphoblastic leukemia in younger and older adults: new drugs and evolving paradigms

Abstract

In the past decade, the available treatments for patients with acute lymphoblastic leukemia (ALL) have rapidly expanded, in parallel with an increased understanding of the genomic features that impact the disease biology and clinical outcomes. With the development of the anti-CD22 antibody-drug conjugate inotuzumab ozogamicin, the CD3-CD19 bispecific T-cell engager antibody blinatumomab, CD19 chimeric antigen receptor T-cell therapy, and the potent BCR-ABL1 tyrosine kinase inhibitor ponatinib, the outlook of ALL in both younger and older adults has substantially improved. The availability of highly effective drugs raised important questions concerning the optimal combination and sequence of these agents, their incorporation into frontline regimens, and the role of hematopoietic stem cell transplantation. In this review, we discuss the rapidly evolving paradigms in the treatment of ALL, highlighting both established and effective regimens, as well as promising new therapies that are being evaluated in ongoing clinical trials. We specifically focus on novel combination regimens in both the frontline and salvage settings that are leading to new standards of care in the treatment of ALL.

High-sensitivity next-generation sequencing MRD assessment in ALL identifies patients at very low risk of relapse

“…Assessment of MRD is imperative for proper risk stratification in ALL and can be used to identify high-risk patients who may be candidates for alternative therapies (eg, blinatumomab or alloSCT for MRD + disease) or low-risk patients for whom treatment de-escalation may be considered. 24 Current consensus recommendations advise that patients without poor-risk pretreatment disease features who rapidly achieve MRD negativity with conventional MRD assays using a sensitivity of at least 1 × 10 −4 do not generally require alloSCT in first remission. 10 For those patients with B-cell ALL who are MRD + at a level of ≥0.1% after initial therapy, MRD-directed therapy with blinatumomab is recommended, with or without subsequent alloSCT.…”

“… 33 Additionally, the advent of blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor T-cell therapies has dramatically improved the outcomes of patients with relapsed/refractory B-cell ALL. 24 Whereas relapsed/refractory ALL was historically considered uncurable without alloSCT, the combination of low-intensity chemotherapy with mini–hyper-CVD with inotuzumab and blinatumomab in patients with Ph − B-cell ALL in first salvage results in a 2-year OS rate of 64% in nontransplanted patients, suggesting that many patients have durable remissions even without alloSCT. 34 Evaluation of MRD negativity using high-sensitivity assays may help to better identify those patients expected to have durable responses, and perhaps cure, with chemoimmunotherapy alone.…”

Characteristics and Outcome of Elderly Patients (>55 Years) with Acute Lymphoblastic Leukemia

“…Novel agents like blinatumomab and inotuzumab ozogamicin are currently being tested in clinical trials and represent promising future therapeutic options, both as frontline and salvage therapy of B-cell precursor ALL patients [40]. Importantly, both antibodies demonstrated clinical benefit irrespective of patient age with an acceptable safety profile [4,[41][42][43].…”

Not all patients with AML over 60 years of age should be offered early allogeneic stem cell transplantation

“… 5 However, in view of expanding therapeutic options, a recent expert Commentary has proposed a more dynamic model. 10 This model proposes to define risk groups on the basis of expected 3-year overall survival (OS), taking molecular data and measurable residual disease (MRD) into consideration, 11-13 and to include patient-related factors such as age, which is a most relevant issue since recommendations by ELN and NCCN cannot easily be extrapolated to patients age 60 years old or older.…”