September 2015, Vol. 2, No. 5
Older Adults with ALL and CAR-T Therapy
Although acute lymphoblastic leukemia (ALL) is predominantly a disease found in children, the incidence peaks again in older adults, who have a high risk of treatment-related mortality. Thus, effective and better tolerated treatment of ALL in older patients is an unmet clinical need, said David I. Marks, MD, PhD, University Hospitals Bristol NHS Foundation Trust, United Kingdom.
Outcomes are poor in older patients and become worse as they age. No new treatments have emerged in 25 years for older patients with ALL. ALL has a different biology in older people compared with children; the disease is more often of B-cell origin, and there is greater coexpression of myeloid antigens, which signal worse prognosis. Cytogenetic changes associated with poor survival are more common in older adults, whereas âgoodâ prognostic lesions are less common than in childhood ALL.
Some of the chemotherapy agents used in childhood ALL are too toxic in adults; for example, reduced renal function can occur with commonly used induction chemotherapy, and conventional doses of anthracyclines can be cardiotoxic.
Older patients should be assessed for comorbidities before selecting treatment, Marks advised. A geriatric assessment can provide information on functional status. This information can be used to individualize therapy, he said.
For example, shortening the duration of neutropenia with granulocyte colony-stimulating factor may improve survival. Myelotoxicities should be considered, and dose reductions of myelotoxic drugs may be necessary; or alternative therapies should be sought; for example, rituximabÂ in patients with CD20-positive B-cell malignancies.
As the aging population increases, the number of geriatric cases of ALL is also expected to increase, underscoring the need for more effective therapies and more prospective clinical trials in the older age group, which is typically excluded from clinical trials.
Conventional chemotherapy can be safely used in patients aged 50 to 65 years with good performance status. However, older and less fit patients cannot tolerate aggressive chemotherapy, and new strategies are needed to improve remission rates.
Marks said that some ongoing trials are looking at new strategies for treating ALL in older patients, such as the UKALL trial in patients aged 60 years and older. Perhaps results from these trials will provide some evidence for better approaches.
Use of CAR-T cells is a novel approach to ALL, and this therapy has produced some remarkable results in both adults and children, even in those with poor prognostic factors who have run out of other treatment options. Basically, CAR-T therapy utilizes the patientâs own T cells, genetically engineered ex vivo to attack the cancer and reinfused into the patientâs body, where they proliferate and become active. Several groups are studying CAR-T therapy, using different vectors and manufacturing strategies.
Michel Sadelain, MD, PhD, Memorial Sloan Kettering Cancer Center, New York City, and colleagues provided the first proof of principle that CAR-modified T cells from the peripheral blood targeted to the CD19 antigen found on the cell surface of most B-cell lymphomas and malignancies could eradicate a broad range of B-cell malignancies, including ALL.
Since then, there have been a number of small studies of CAR-T therapy in children and adults with ALL. The biggest safety concern with CAR-T therapy includes the potential for severe cytokine release syndrome (CRS), which can result in B-cell aplasia. Researchers have learned to manage this with intravenous immunoglobulin, but this can remain a problem for patients with long-term persistence of CAR-T once the cells are reinfused.
Another concern with severe CRS is intensive antitumor responses mediated by a number of activated T cells that can manifest as high fever, hypertension, respiratory distress, and/or neurologic symptoms such as confusion, aphasia, or global encephalopathy. This is treated with steroids, an interleukin-6 receptor blocker, vasopressors, and/or supportive care therapy in an intensive care unit.
According to Sadelain, CAR-T is expected to become part of the armamentarium for B-ALL and other B-cell malignancies.
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