Recent FDA Approvals for ALL a “Watershed” MomentLeukemia, Web Exclusives
Atlanta, GA—The past few years have witnessed significant progress in the treatment of several hematologic malignancies, and truly paradigm-changing therapies have recently emerged in acute lymphoblastic leukemia (ALL). At ASH 2017, Crystal L. Mackall, MD, Co-Director, Immunology & Immunotherapy of Cancer Program, Stanford University, CA, discussed the FDA approvals of 2 important treatments for patients with B-cell precursor ALL.
Besponsa for B-Cell ALL in Adults
In August 2017, the FDA approved inotuzumab ozogamicin (Besponsa), a CD22-directed antibody drug conjugate for the treatment of relapsed or refractory B-cell precursor ALL in adults. In a study of relapsed or refractory B-ALL in adults, inotuzumab ozogamicin showed an impressive single-agent remission induction rate of 81% versus 29% with standard chemotherapy (Kantarjian HM, et al. N Engl J Med. 2016;375:740-753). Despite these “very promising” results, said Dr Mackall, excitement has been tempered by liver toxicity.
A related compound, gemtuzumab ozogamicin (Mylotarg, now approved for acute myeloid leukemia), had demonstrated similar activity in ALL, but its benefit was diminished by veno-occlusive disease (VOD), which required hematopoietic stem-cell transplant in many patients.
“A similar pattern emerged with inotuzumab ozogamicin,” said Dr Mackall. VOD occurred in 11% of patients receiving this drug versus 1% in those who received chemotherapy. “These results further implicate ozogamicin as a risk factor for VOD, and suggest that these patients will be at heightened risk when they undergo consolidation therapy if it comes in the form of hematopoietic stem-cell transplant.”
Kymriah First FDA-Approved CAR T-Cell Therapy
In August 2017, the FDA approved tisagenlecleucel (Kymriah), the first chimeric antigen receptor (CAR) T-cell therapy, for B-cell precursor ALL that is refractory or in second or later relapse in young patients <25 years.
Although incremental advances have yielded big payoffs in pediatric ALL in the past 50 years, chemoresistance has prevented further improvements, said Dr Mackall. The substantial incidence of late effects, especially central nervous system (CNS) toxicity, is a major problem facing clinicians. The FDA approval of tisagenlecleucel, the first gene therapy approved in the United States, represents a “watershed moment in cancer immunotherapy,” she said. “This is clearly some kind of therapeutic that we’ve never seen before,” she added.
Reacting to this approval, Scott Gottlieb, MD, FDA Commissioner, said, “We’re witnessing a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer. New technologies such as gene and cell therapies have the potential to transform medicine.”
Dr Mackall emphasized that despite their complexity and cost, CAR T-cell therapies are poised for a major impact in B-ALL. This impact will lead to eradication of chemoresistant leukemia; improve cell manufacturing to provide these drugs to all patients with cancer; reduce chronic toxicity for B-cell ALL; and reduce late adverse effects from CNS-directed therapies.
Several studies using CAR T-cells have demonstrated that CD-19 CAR T-cells yield high remission rates in children with B-cell ALL.
“What’s exciting to me is that the highest-risk patients—those with primary refractory, Philadelphia chromosome–positive, or ALL-rearranged disease—continually see high rates of remission,” she said. “The important point is that chemoresistance does not equate with immune resistance. Therefore, CARs provide a potent new tool to add to the multiagent treatment regimen for chemoresistant B-ALL.”
A major question facing clinicians is how best to integrate CAR T-cell therapy with allogeneic stem-cell transplant.
“When is it appropriate to recommend or defer allogeneic stem-cell transplant to patients rendered into remission with CAR therapy?” Dr Mackall asked. “There are many different answers to that question, and we’re going to need more data to figure that out.”
Integrating CAR T-cell therapies with recently approved monoclonal antibodies, such as blinatumomab (Blincyto) and inotuzumab ozogamicin, is another issue.
“Emerging clinical experience strongly suggests that previous blinatumomab increases the risk of CD19-negative relapse following CD19-CAR therapy, and similar results are emerging with inotuzumab ozogamicin and CD22-CAR therapy,” she said. “Rather than these therapies synergizing with each other…clinicians may be reducing the power of a CAR T-cell by pretreating patients with an antibody targeting the same antigen.”
On January 9, 2020, the FDA approved avapritinib (Ayvakit; Blueprint Medicines), a kinase inhibitor, for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutations, including PDGFRA D842V mutations.
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