Acute Lymphobastic Leukemia (ALL): Highlights from ASH 2020

From 05th to 08th December 2020, the Acute Leukemia Advocates Network (ALAN) attended the virtual 62nd ASH Annual Meeting and Exposition.

Samantha Nier, Network Manager reports on the ALL sessions she attended and this comes in addition to has been posted on social media (https://twitter.com/AcuteLeuk)

Innovations in treatment options for ALL has improved patient outcomes with the optimization of multi-agent chemotherapy regimens through the use of asparaginase compounds, and more recently, the validation of newer agent classes, such as tyrosine kinase inhibitors, antibody-drug conjugates, bispecific antibodies, and adoptive cell therapy agents, has also led to better outcomes and enhanced care.

The development of antibody therapy in ALL and its integration into care can be considered a model for how to enhance standard treatment protocols over a range of settings, including induction/consolidation strategies prior to transplant, and as a way to induce deep, minimal residual disease-negative responses.

1- Inotuzumab Ozogamicin – CD22-directed antibody-drug conjugate indicated for the treatment of adults with relapsed or refractory (R/R) B-cell precursor ALL.

2- Blinatumomab –  bispecific CD19-directed CD3 T-cell engager indicated for the treatment of adults and children with B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% or with R/R B-cell precursor ALL.

Next steps with antibody therapy: combination, sequencing and beyond. 

Several studies are currently ongoing and are showing the following:

• combination of chemotherapy with novel monoclonal antibodies are safe and effective in both R/R and newly diagnosed ALL.
• these combinations lead to high rates of MRD negativity, which may improve outcomes compared with sequential single-agent therapies
• chemotherapy-free frontline regimen are now being evaluated in Ph+ALL and in older adults with newly diagnosed B-ALL.

In pediatric ALL, the overall survival has not improved in the last decade and the dose intensity of conventional chemotherapy has been pushed to the limit. But there are also some recent advances in the management of pediatric ALL: 

• targeted therapies with molecular therapeutics and immunotherapy promises to replace toxic chemotherapy and improve cure rate and quality of life of the patients
• while CAR-T-cell therapy is indicated for B-ALL patients with second or more relapses or refractory disease, antibody-based therapy improves outcomes for patients in first relapse and should be tested in newly diagnosed B-ALL patients with unfavorable genotypes. 
• as conventional therapy, targeted therapies with non-overlapping toxicities should be combined rationally to synergistically kill leukemia cells. 

Minimum (Measurable) Residual Disease  (MRD) in ALL 

MRD testing is a powerful way to assess response to treatment and evaluate prognosis. 

• what is a sufficient MRD test in ALL ? ALL MRD tests should be performed by laboratories using standardized and validated MRD assays with a sensisity of at last 10-4.
• how do the available ALL MRD testing techniques differ ?
• when should MRD be assessed ?

Some clinical studies with innovative chemotherapy and immunotherapy strategies in frontline and relapse disease are going and are showing some (promising) results:  

• INITIAL-1 trial: Open Label Phase II Study to Evaluate the Efficacy and Safety of Inotuzumab Ozogamicin for Induction Therapy Followed By a Conventional Chemotherapy Based Consolidation and Maintenance Therapy in Patients Aged 56 Years and Older with ALL
• A Randomized, Controlled Phase 3 Trial: Superior Event-Free Survival with Blinatumomab Versus Chemotherapy in Children with High-Risk First Relapse of B-Cell Precursor ALL
• Pre-CAR Blinatumomab Is Associated with Increased Post-CD19 CAR Relapse and Decreased Event Free Survival

Some other studies investigating targeted and CAR-T cell therapies are also ongoing with some results: 

• Phase II study Hyper-CVAD and Sequential Blinatumomab in Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell ALL
• Phase I/II Study of the Ponatinib, Venetoclax and Dexamethasone for Patients with Relapsed or Refractory Ph+ ALL
• Venetoclax and Navitoclax in Pediatric Patients with ALL and Lymphoblastic Lymphoma
• ALLCAR19: Updated Data Using AUTO1, a Novel Fast-Off Rate CD19 CAR in R/R B-Cell ALL and Other B-Cell Malignancies
• A Phase I Study of UCART22 (allogeneic engineered T-cells expressing anti-CD22 Chimeric Antigen Receptor) in Adult Patients with R/R CD22+ B-Cell ALL
• A Phase II Study of Single-Agent Inotuzumab Ozogamicin in Pediatric CD22-Positive R/R ALL

The results of those studies are for the time being interim data or from early phase studies. We’ll be monitoring for more data as they come and we’ll be sharing those.