Results from a phase II study presented by Nicholas J. Short, MD, and colleagues at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 464) showed that first-line treatment with a regimen of chemotherapy combined with the monoclonal antibody blinatumomab resulted in increased survival for patients who were newly diagnosed with Philadelphia chromosome–negative B-cell acute lymphoblastic leukemia (ALL). Patients treated with the regimen also achieved a high rate of measurable residual disease (MRD) negativity.
“The best opportunity to cure any acute leukemia is by giving the most effective therapy in the front-line setting,” said Dr. Short, Assistant Professor of Leukemia at The University of Texas MD Anderson Cancer Center. “We are very encouraged that every patient on the study achieved a complete remission, and 97% achieved MRD negativity, which is highly associated with better outcomes.”
Nicholas J. Short, MD
Current Therapies
Standard treatment for patients with Philadelphia chromosome–negative B-cell ALL is combination chemotherapy, which has a high rate of treatment failure and complications. Current therapies for ALL can result in remission rates of up to about 90%. However, many patients relapse, leading to long-term survival rates of 50% or less. Finding new treatment options that can improve response and survival for these patients is critical.
Immunotherapy using monoclonal antibodies, such as blinatumomab, encourages changes in the body's immune system and interferes with the ability of tumor cells to grow and spread. Blinatumomab has two components: one that targets CD3, on the T cells, and one that targets CD19, which is overexpressed in most cases of B-cell ALL. Previous clinical trials have shown blinatumomab to be effective in improving overall survival in the relapsed or refractory setting and it has been proven to clear up MRD, as well.
“Although the survival data is early, it is promising, with a 2-year survival of 80%. This is particularly important, as about a third of these patients had high-risk features,” said lead study author Elias Jabbour, MD, Professor of Leukemia at MD Anderson. “We are encouraged that we can decrease the amount and duration of chemotherapy for patients and hope that these results will translate to long-term survival and increased cure compared to standard chemotherapy regimens.”
Study Details
The trial enrolled 38 patients aged 14 to 59 with newly diagnosed Philadelphia chromosome–negative B-cell ALL, 34 of whom were able to be evaluated in the study. Patients could not have received more than one prior cycle of chemotherapy and were required to have a performance status of ≤ 3, total bilirubin ≤ 2 mg/dl, and creatinine ≤ 2 mg/dl.
Trial participants were 55% White, 32% Hispanic, 5% Black, 3% Asian, and 5% other. At least one high-risk feature was present in 19 patients (56%), including TP53 mutation in 10 patients (17%), CRLF2+ in 6 patients (19%), and an adverse-risk karyotype in 12 patients (32%).
Patients received two cycles of hyperfractionated cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, and dexamethasone (hyper-CVAD) chemotherapy alternating with two cycles of high-dose methotrexate and cytarabine, followed by four cycles of blinatumomab at standard doses. The maintenance phase consisted of 12 monthly cycles of daily mercaptopurine, monthly vincristine, weekly methotrexate, and monthly pulses of prednisone (POMP) with three additional cycles of blinatumomab.
Results
All patients in the study experienced at least one adverse event, which was expected with the hyper-CVAD regimen. Four patients developed cytokine release syndrome, which resolved with corticosteroids and interruption of blinatumomab.
Thirty-one percent of patients had a blinatumomab-related neurologic event, including grade 2 seizure in one patient, grade 1 tremor in two patients, grade 3 ataxia in one patient, and grade 2 encephalopathy and dysphasia in one patient. All other neurologic events were manageable, reversible, and did not alter the planned treatment.
Relapses occurred in 13% of patients, but no relapses were observed in patients without baseline high-risk features or in any patients beyond 2 years. Twelve patients underwent an allogeneic stem cell transplant, and 17 patients remain in continuous remission.
The next stage of this study will incorporate inotuzumab ozogamicin into the regimen for the next 40 patients enrolled in the trial. Inotuzumab ozogamicin is an anti-CD22 antibody drug that attaches to CD22, which is highly expressed in B lymphoblasts, and then delivers the toxin directly to the ALL cells. While these findings need to be confirmed in larger studies, the data suggests that blinatumomab can improve treatment response for patients with Philadelphia chromosome–negative B-cell ALL.
“Our goal now is to see if we can do hyper-CVAD with blinatumomab and adding inotuzumab ozogamicin to get even better results,” said Dr. Short said. “We believe this will decrease chemotherapy-related toxicity, minimize MRD, further decrease reliance on stem cell transplants, and improve long-term outcomes for these patients.”
Disclosure: This research was supported by the National Cancer Institute (P30 CA016672), Amgen, and Pfizer. For full disclosures of the study authors, visit ash.confex.com.
