Two investigational agents—inotuzumab and ofatumumab—show promise when combined with cytotoxic chemotherapy drugs for the treatment of acute lymphoblastic leukemia (ALL) in adults.
The early results of two ongoing clinical trials, which are available only at The University of Texas MD Anderson Cancer Center, were reported in June at the 2014 American Society of Clinical Oncology Annual Meeting by Elias Jabbour, M.D., an associate professor in the Department of Leukemia, and colleagues.
Dr. Jabbour said the studies are important because they provide a new avenue of treatment for adult ALL patients, who tend to have more aggressive disease, lower tolerance for chemotherapy, and worse outcomes than do children with the disease. “Although great success has been seen in the treatment of pediatric ALL, unfortunately outcomes for adults have lagged behind,” Dr. Jabbour said. The cure rates for children and adults with ALL are around 90% and 40%, respectively.
Monoclonal antibodies that target surface antigens such as CD20 and CD22 on ALL cells have become a mainstay in the treatment of ALL. The standard of care for patients in whom CD20 is expressed on at least 20% of ALL cells is the anti-CD20 monoclonal antibody rituximab combined with cytotoxic chemotherapy. However, rituximab is not effective in patients whose tumor cells have lower levels of CD20 expression or in the tiny percentage of patients whose disease does not express CD20 at all.
Second-generation monoclonal antibodies such as inotuzumab and ofatumumab could extend the use of antibody-chemotherapy combinations to a broader group of ALL patients.
When the CD22 inhibitor inotuzumab ozogamicin was found to be active as a single agent against ALL in early studies, researchers saw the opportunity to reduce the doses of cytotoxic chemotherapy drugs. “In the beginning, we thought about treating elderly patients with the drug because many elderly patients cannot tolerate chemotherapy very well,” Dr. Jabbour said. “In one study, treatment-naïve patients 60 years or older with ALL were given chemotherapy at half the standard dose plus inotuzumab. Responses were excellent.”
Those results led to the current study—led by Hagop Kantarjian, M.D., a professor in and chair of the Department of Leukemia—in which treatment-naïve ALL patients 60 years or older or patients of any age with relapsed or refractory ALL are given inotuzumab and low-intensity cytotoxic chemotherapy. Patients in the study receive 8 cycles of a chemotherapy regimen that comprises reduced doses of cyclophosphamide, dexamethasone, methotrexate, and cytarabine; during the first 4 cycles, patients are also given rituximab and inotuzumab. Patients then receive maintenance therapy with mercaptopurine, methotrexate, vincristine, and prednisone (POMP) for 4 years.
At the trial’s interim analysis, the overall response rates for patients with newly diagnosed ALL and relapsed/refractory ALL were 95% and 75%, respectively. “We have not seen significant adverse effects, and the 1-year survival rate was about 80%,” Dr. Jabbour said.
The anti-CD20 molecule ofatumumab, which binds to CD20 at a site different from that of rituximab, is already approved for the treatment of chronic lymphoblastic leukemia. Dr. Jabbour is the principal investigator of a phase II clinical trial of cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and cytarabine (hyper-CVAD) plus ofatumumab as a frontline treatment for patients with ALL.
In the study, patients with CD20-positive ALL who are newly diagnosed or have undergone 1 cycle of chemotherapy receive the first 4 cycles of the hyper-CVAD regimen with ofatumumab followed by 4 cycles of hyper-CVAD without ofatumumab. Patients then receive maintenance therapy with POMP for 30 months. The maintenance therapy is interrupted with intensification therapy comprising methotrexate plus pegaspargase in months 6 and 18 and hyper-CVAD plus ofatumumab in months 7 and 19.
Of the first 25 patients enrolled in the study, 24 were in complete remission as of June. Dr. Jabbour said there were no safety concerns associated with the treatment. “Obviously the follow-up is short at 14 months,” he said. “But if these results are maintained a year from today, that will be a major breakthrough in the treatment of patients with ALL.”
Future is bright
In addition to inotuzumab and ofatumumab, other monoclonal antibodies, such as obinutuzumab, blinatumomab, SGN-CD19A, and epratuzumab, are being investigated for the treatment of ALL in clinical trials at MD Anderson and other institutions. Dr. Jabbour is optimistic that combinations of such agents and cytotoxic chemotherapy drugs will improve cure rates for pediatric and adult ALL patients alike. He said, “Going forward with the antibodies we have available to us, the future is bright for ALL patients.”
For more information, contact Dr. Elias Jabbour at 713-792-4764.
OncoLog, September 2014, Volume 59, Issue 9
To learn more about the ongoing clinical trials of chemotherapy plus monoclonal antibodies for the treatment of ALL, visit www.clinicaltrials.org and select study No. 2010-0991 (inotuzumab) or 2010-0708 (ofatumumab).