Year in Review: Acute Lymphoblastic Leukemia

The past year in acute lymphoblastic leukemia (ALL) research was marked by studies examining different ways of using chimeric antigen receptor (CAR) T-cell therapy, as well as efforts to de-intensify treatment.

Tisagenlecleucel Effective in Youngest Kids

The ELIANA study previously showed that a single infusion of the CAR T-cell therapy tisagenlecleucel (Kymriah) provided durable remission with long-term persistence in pediatric patients ≥3 years of age and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects.

This year, a retrospective cohort study of 38 children younger than 3 years with relapsed or refractory B-cell ALL — most of whom had infant ALL — showed that tisagenlecleucel is effective in these younger patients.

The overall survival (OS) rates at 6 and 12 months after infusion with the CAR T-cell therapy were 88% and 84%, respectively, while event-free survival (EFS) rates were 75% and 69%, reported André Baruchel, MD, of Hôpital Universitaire Robert Debré and Université Paris, and colleagues in Lancet Haematology.

Adverse events included cytokine release syndrome, which occurred at any grade in 21 of 35 patients and at grade 3 or higher in five patients, and neurotoxicity at any grade in nine patients, which was not severe in any patient.

In an accompanying editorial, Haneen Shalabi, MD, and Nirali N. Shah, MD, both of the National Cancer Institute in Bethesda, Maryland, noted that the results “emerging from the largest study of our knowledge to date in infants and very young children receiving tisagenlecleucel, serve to fill a key gap — particularly because the global registration trial (ELIANA) excluded children aged younger than 3 years.”

Disease Burden Affects Outcomes

A retrospective study published in the Journal of Clinical Oncology looking at the “real-world” outcomes in children, adolescents, and young adults with relapsed/refractory pediatric B-cell ALL treated with tisagenlecleucel showed that patients with a high disease burden had inferior outcomes. These patients had a 12-month OS rate of 58% and an EFS rate of 31% compared with rates of 85% and 70% for patients categorized as having a low disease burden and rates of 95% and 72% for those with undetectable disease.

“I would encourage oncologists to consider CAR T-cell therapy early in the disease course for patients with relapsed and refractory ALL,” study author Theodore W. Laetsch, MD, of Children’s Hospital of Philadelphia, told MedPage Today. “Hopefully, we can achieve better outcomes for our patients by treating before their leukemia becomes so unresponsive that it can’t be controlled.”

Co-Administering CD19- and CD22-Directed CAR T-Cell Therapies

Chinese researchers hypothesized that co-administration of CD19- and CD22-targeted CAR T cells would improve efficacy based on the principle that combination therapy forestalls the development of drug resistance in ALL, as well as a preclinical model showing that simultaneous targeting may reduce the risk of antigen loss. Moreover, they suggested that co-administration would avoid repeated lymphodepleting chemotherapy that eradicates CD19 CAR T cells.

Their study, published in the Journal of Clinical Oncology, showed that co-administration of CD19- and CD22-directed CAR T-cell therapy in 194 children with relapsed or high-risk B-cell ALL led to a complete remission rate of 99%, with 12-month EFS and OS rates of 73.5% and 87.7%, respectively.

“These results appeared to be better than those of real-world experience with tisagenlecleucel,” the authors wrote. “We attributed our favorable results partly to the simultaneous administration of two different CAR T cells to enhance early eradication of leukemia clones, thereby impeding the development of resistance.”

They noted that longer follow-up is needed to determine the durability of the response to the therapy.

‘Better Than Expected’ Outcomes With Reduced-Intensity Conditioned Transplant

In a study of nearly 250 older adults with high-risk ALL in first remission, reduced-intensity conditioned allogeneic hematopoietic stem cell transplantation (HSCT) with fludarabine, melphalan, and alemtuzumab resulted in EFS and OS rates of 46.8% and 54.8% at 4 years, reported David Marks, MBBS, PhD, of the University Hospital Bristol NHS Trust in England, and colleagues in Lancet Haematology.

Furthermore, these survival rates were achieved with relatively low rates of chronic graft-versus-host disease and transplant-related mortality.

This study “provides practice-informing evidence for the role of reduced-intensity conditioned allogeneic HSCT in older adults with acute lymphoblastic leukemia in first complete remission,” they concluded.

Blinatumomab as Frontline Therapy for ALL

While blinatumomab (Blincyto) is effective in relapsed or refractory B-cell ALL, and results in high rates of minimal residual disease negativity, the objective of this recent phase II study was to determine if incorporating blinatumomab into front-line therapy for ALL could improve outcomes.

Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center in Houston, and colleagues found that the addition of blinatumomab — a CD19/CD3 bispecific T-cell engager — to frontline chemotherapy (hyperfractionated cyclophosphamide, vincristine [Oncovin], doxorubicin, and dexamethasone, alternating with high-dose methotrexate and cytarabine) resulted in high rates of minimal residual disease negativity, sustained responses, and estimated 3-year relapse-free survival and OS rates of 73% and 81%, respectively, in adults with newly diagnosed Philadelphia chromosome-negative B-cell ALL.

“These encouraging results were seen despite fewer cycles of chemotherapy and a shorter duration of therapy than most standard protocols for the treatment of acute lymphocytic leukemia,” Jabbour and colleagues noted.

Reducing Cranial Radiotherapy in T-Cell ALL

In the Children’s Oncology Group Trial AALL1231, investigators led by David T. Teachey, MD, of the Children’s Hospital of Philadelphia, evaluated the addition of the proteasome inhibitor bortezomib (Velcade) to chemotherapy in children and young adults with newly diagnosed T-cell ALL (T-ALL) and T-cell lymphoblastic lymphoma, and found that systematic therapy intensification basically allowed for the elimination of cranial radiotherapy in patients with T-ALL.

“There are significant side effects from cranial radiotherapy, both short-term and long-term,” Teachey told MedPage Today. “Radiation in young patients affects development of the brain and impacts neurocognitive outcomes, including attention, concentration, and a slight loss in IQ. Prior to this study, 90% of young T-cell leukemia patients in the U.S. received cranial radiotherapy. We eliminated this radiation in all but 10% of patients.”