The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades

Abstract

Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B Philadelphia chromosome-negative ALL, the integration of blinatumomab and inotuzumab into the frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories. Our future strategy is to evaluate the early integration of both immunotherapy agents, inotuzumab and blinatumomab, with low-dose chemotherapy (dose-dense mini-Hyper-CVD-inotuzumab-blinatumomab) into the frontline setting followed by CAR T cells consolidation in high-risk patients, without any further maintenance therapy. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year survival rate to 50%. Among patients ≥ 65–70 years, the mortality in complete remission (CR) is still high and is multifactorial (old age, death in CR with infections, development of myelodysplastic syndrome or acute myeloid leukemia). A chemotherapy-free regimen with inotuzumab and blinatumomab is being investigated. The assessment of measurable residual disease (MRD) by next-generation sequencing (NGS) is superior to conventional assays, with early MRD negativity by NGS being associated with the best survival. We anticipate that the future therapy in B-ALL will involve less intensive and shorter chemotherapy regimens in combination with agents targeting CD19 (blinatumomab), CD20, and CD22 (inotuzumab). The optimal timing and use of CAR T cells therapy may be in the setting of minimal disease, and future trials will assess the role of CAR T cells as a consolidation among high-risk patients to replace allogeneic SCT. In summary, the management of ALL has witnessed significant progress during the past four decades. Novel combination regimens including newer-generation BCR::ABL1 TKIs and novel antibodies are questioning the need and duration of intensive chemotherapy and allogeneic SCT.

Inotuzumab ozogamicin for the treatment of adult acute lymphoblastic leukemia: past progress, current research and future directions

“…Along with the blinatumomab and CAR T-cells, the clinical development of INO has been a major contributor to improving outcomes of adult ALL over the past decade [ 49 ]. While INO has been shown to be more effective than conventional cytotoxic chemotherapy in relapsed/refractory B-cell ALL, its greatest potential is as combination therapy in both the frontline and salvage settings.…”

Galectin-9 in cancer therapy: from immune checkpoint ligand to promising therapeutic target

“…This suggests a potential shared mechanism involving Gal-9 in different leukemia subtypes. Studies are currently underway to explore the early integration of immunotherapeutic agents such as inotuzumab and blinatumomab with low-dose chemotherapy (dose-dense mini-Hyper-CVD-inotuzumab-blinatumomab) in the frontline setting for the treatment of B-ALL ( Jabbour et al, 2023 ). Following this approach, CAR T-cell consolidation at high doses without maintenance therapy is being proposed for at-risk patients Inhibition of Gal-9 represents an unexplored approach that could potentially improve the prognosis of patients with B-ALL and other leukemia subtypes, particularly in the presence of obesity-related factors.…”

Diagnostic and therapeutic advances in adults with acute lymphoblastic leukemia in the era of gene analysis and targeted immunotherapy

“…With the introduction of imatinib in 2000 (since 2001 in Korea) [ 19 – 25 ], dasatinib in 2006 (since 2008 in Korea) [ 26 – 28 ], and ponatinib in 2010 (since 2016 in Korea) [ 29 – 32 ], the remission rates have improved to > 90% and long-term survival outcomes have improved ( Fig. 1 ) [ 13 ].…”

“…ALL, acute lymphoblastic leukemia; OS, overall survival; BLINA, blinatumomab; PONAT, ponatinib; HCVAD, hyper-CVAD; DASAT, dasatinib; IMAT, imatinib; TKI, tyrosine kinase inhibitor; R/R, relapsed or refractory. Figure 1A adapted from Jabbour et al J Hematol Oncol 2023;16:22 [ 13 ].…”

“…The treatment outcomes of Ph-positive ALL have been improved with the introduction of tyrosine kinase inhibitors (TKIs) in 2000, but the 5-year DFS is 50–60% in Korea although the complete remission (CR) rate is > 90%. However, incorporating ponatinib into frontline therapy results in improved survival outcomes almost similar to those of pediatric ALL and has opened the possibility of chemotherapy-free approaches [ 13 ]. Treatment of B-cell precursor ALL (B-ALL) has been accelerating since the 2010s with the introduction of blinatumomab, inotuzumab ozogamicin (INO), and anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies, and the therapeutic paradigm is largely changing.…”