Treatments targeting immune responses against solid tumors have led to dramatic improvements in patient outcomes, but the role for immunotherapy in the treatment of acute leukemia is still being defined. At the National Comprehensive Cancer Network 12th Annual Congress: Hematologic Malignancies, David G. Maloney, MD, PhD, discussed the latest immunotherapeutic approaches for the treatment of acute lymphocytic leukemia (ALL), including chimeric antigen receptor (CAR) T cells, which demonstrated complete response in 94% of heavily pretreated patients in one clinical trial. According to Dr Maloney, of the Fred Hutchinson Cancer Research Center and the Immunotherapy Clinic at Seattle Cancer Care Alliance, in Seattle, WA, better sequencing and combinations of immunotherapies will likely decrease the need for allogeneic hematopoietic cell transplantation.
Rituximab for Adult CD20-Positive ALL
As Dr Maloney reported, rituximab, an anti-CD20 monoclonal antibody, was approved 20 years ago by the FDA for the treatment of CD20-positive lymphocytes, but it has not been approved for ALL. When compared with standard chemotherapy, however, the addition of rituximab to chemotherapy has been shown to improve outcomes in CD20-positive, Philadelphia chromosome–negative ALL (N Engl J Med. 2016;375:1044-1053). Results from the randomized trial showed an increase in 2-year event-free survival rates of 52% to 66% (P = .04) and decreased rates of relapse. Investigators also observed trends for improved overall survival and more rapid clearing of minimal residual disease. According to Dr Maloney, there were fewer allergic reactions to asparaginase in the rituximab group, as well.
“Given the improvement in survival and relapse rates, rituximab is certainly a reasonable treatment approach for clinicians to take in this population,” said Dr Maloney.
Inotuzumab ozogamicin, an antibody drug conjugate directed against the CD22-positive antigen present on B cells in all patients with mature B-ALL and most patients (>90%) with precursor B-ALL, was approved by the FDA in August 2017. A phase 3 trial of adults with relapsed/refractory ALL (N = 326) showed that patients randomized to inotuzumab ozogamicin had a significantly higher rate of complete remission compared with standard chemotherapy (80.7% vs 29.4%; P <.001). What’s more, complete remissions occurred irrespective of the duration of first remission, patient age, and the phase of salvage treatment (N Engl J Med. 2016;375:740-753).
“All groups retained statistical significance in favor of inotuzumab ozogamicin,” said Dr Maloney, who noted that even patients in whom stem cell transplantation had failed had high rates of complete remission.
Despite the high rates of complete remission, however, long-term follow-up was described as “somewhat disappointing.” At 10 to 12 months, only a minority of patients were still in remission, and progression-free survival decreased rapidly.
“Survival is somewhat dismal in this group,” said Dr Maloney. “At 2 years, the proportion of cured patients is only in the 20% to 25% range.”
Blinatumomab, a bispecific antibody combining anti-CD19 with anti-CD3, has also demonstrated activity in ALL. In a phase 3 trial of adult patients with relapsed or refractory B-cell precursor ALL (N Engl J Med. 2017;376:836-847), treatment with blinatumomab resulted in significantly longer overall survival than chemotherapy (7.7 vs 4.0 months; P =.01).
In addition, when compared with standard chemotherapy, remission rates within 12 weeks after treatment initiation were also significantly higher in the blinatumomab group, and treatment resulted in a higher rate of event-free survival at 6 months than chemotherapy (31% vs 12%; P <.001).
However, whereas there is a clear overall benefit compared with conventional therapy, according to Dr Maloney, the response rates are moderate, and blinatumomab is still not curing the vast majority of disease. Moreover, said Dr Maloney, the 4-week continuous infusion can be cumbersome for patients, and there are significant toxicities.
CAR T Cells
Modification of T cells via CAR is one of the hottest topics in oncology and has already led to a multitude of new therapies. As Dr Maloney explained, the key is the target of the CAR T cells. At the Fred Hutchinson Cancer Research Center, Dr Maloney and colleagues have treated over 200 patients on protocol 2639, which is evaluating CD19 CAR T cells manufactured from defined CD8-positive and CD4-positive T-cell subsets (J Clin Invest. 2016;126:2123-2138). The study has included 36 adults with B-cell ALL following lymphodepleting chemotherapy.
According to Dr Maloney, these were heavily pretreated patients, many of whom would not qualify for further trials. Despite the advanced stage of disease, however, 94% of patients had a complete response, and IGH locus deep sequencing found that the index clone was undetectable in 65% of patients. Dr Maloney described the product as “remarkably potent” but cautioned that CAR T-cell therapy should be administered in centers with experience due to the serious side effects of cytokine release syndrome and neurotoxicity.