An investigational immunotherapy is improving outcomes in difficult-to-treat acute lymphoblastic leukemia (ALL) and showing promise in other cancers, as well.
Blinatumomab (Blincyto), the first U.S. Food and Drug Administration (FDA)-approved bispecific T-cell engager (BiTE), has demonstrated activity in ALL patients with minimal residual disease and disease that has relapsed or is refractory to chemotherapy. According to data presented at a City of Hope symposium—How the Experts Treat Hematologic Malignancies—activity is irrespective of chemosensitivity or prior allogeneic stem cell transplantation, and toxicity is both manageable and reversible.1
Blinatumomab is an ideal drug to combine with other novel agents, but a better understanding of how ALL genetics and host immune profiles correlate with response is needed.— Ibrahim T. Aldoss, MD
“Blinatumomab is potentially curative for minimal residual disease–positive ALL, and it also serves as a bridging therapy for allogeneic stem cell transplant in advanced ALL,” said Ibrahim T. Aldoss, MD, Assistant Clinical Professor of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California.
As Dr. Aldoss reported, long-term survival following ALL relapse has been poor historically (~10%),2 but recent advances in immunotherapy are generating buzz—along with improved outcomes.
“In the past couple of years, we’ve been seeing very active immunotherapeutic agents in the relapse setting. It’s a very exciting time,” said Dr. Aldoss, “but T-cell therapy is still hampered by a large number of immune escape mechanisms.”
BiTE is an antibody construct composed of two monoclonal antibodies: One side is CD3, a co-receptor routinely expressed in T cells, and the other side is an antigen of the targeted cancer cell. CD19 was chosen as the tumor-associated antigen for blinatumomab, said Dr. Aldoss, because it is expressed on the vast majority of B-cell malignancies, including ALL.
Blinatumomab is FDA-approved for relapsed/refractory, Philadelphia chromosome–negative B-cell ALL. Although activity has been seen in Philadelphia chromosome–positive ALL, blinatumomab is not yet approved in this setting.
Minimal Residual Disease
In the long-term follow-up to the phase II BLAST trial, ALL patients with persistent or recurrent minimal residual disease had a complete molecular response of 78%.3 Response to therapy was observed regardless of age, sex, line of treatment, and burden of minimal residual disease, and consolidation with transplant following blinatumomab response in this setting did not influence survival.
“Worse survival outcomes have long been observed in minimal residual disease–positive ALL patients, especially those who have not undergone transplant, but this study shows that blinatumomab can play an important role in this setting,” said Dr. Aldoss. He noted that median overall survival was more than 3 years, even among patients who did not undergo consolidation with transplant. “We can conclude from these data that blinatumomab can cure patients with minimal residual disease in this setting.”
Phase III Randomized Study
In a multicenter, open-label trial,4 405 adult patients with relapsed or refractory B-precursor, Philadelphia chromosome–negative ALL, were randomized to receive blinatumomab (n = 271) or standard chemotherapy (n = 134).
Median overall survival was 7.7 months (95% confidence interval [CI] = 5.6–9.6 months) in the blinatumomab group vs 4.0 months (95% CI = 2.9–5.3 months) in the chemotherapy group (hazard ratio [HR] = 0.71, P = .01). In addition, overall response to blinatumomab was 44%, compared to 25% in the standard-of-care arm (P < .001). Finally, in an analysis censoring data at the time of allogeneic stem cell transplantation, median overall survival was 6.9 vs 3.9 months (HR = 0.66, P = .004).
“Following a prespecified interim analysis, the trial was stopped early based on the clear benefit of blinatumomab treatment,” said Dr. Aldoss.
Predictors of Response
Analysis of a separate phase II study showed that response to blinatumomab in relapsed or refractory B-cell ALL was irrespective of prior chemosensitivity or prior allogeneic stem cell transplant.5 Patients who had undergone prior transplant had a complete response rate of 45% (n = 64) vs 42% (n = 125) for those who had not received prior transplant. Elderly patients also had comparable outcomes when treated with blinatumomab.
The only factor that predicted response, said Dr. Aldoss, was the amount of disease prior to treatment. If bone marrow contained less than 50% blasts, the complete response rate increased to 73%. For patients with more than 50% blasts in the marrow, however, the complete response rate fell to 29%.
Response to blinatumomab also appears higher in patients with lower pretreatment marrow T-regulatory cells, higher platelet counts, and higher peak of interleukin-10 levels after initiating therapy. Given the disparity in response in patients with a high disease burden, investigators are considering cytoreductive treatments prior to blinatumomab, Dr. Aldoss reported.
Retreatment with blinatumomab is also feasible among relapsed CD19-positive ALL patients. A study by Topp et al found that 36% (4/11) of patients who had relapsed achieved a complete response on blinatumomab, with 1 patient re-treated for the second time achieving a third remission.6
Nevertheless, Dr. Aldoss emphasized that blinatumomab is not a long-term solution in this setting. “With few exceptions, patients who respond to blinatumomab inevitably relapse and must be taken to transplant quickly,” he said. “It’s a good drug for bridging to transplant for patients with chemorefractory disease.”
Toxicities Manageable and Reversible
As Dr. Aldoss reported, severe cytokine-release syndrome usually occurs in the relapsed/refractory setting, especially with higher disease burden. However, when pretreatment with dexamethasone (20 mg intravenously 1 hour before starting each cycle) and stepwise escalation were employed in this setting, only 2% of patients experienced grade III cytokine-release syndrome, and blinatumomab activity was not compromised. Severe cytokine-release syndrome is uncommon in patients treated for minimal residual disease, Dr. Aldoss added.
Central nervous system toxicities were more common, however, with 22% of patients experiencing dose-limiting or grade III/IV toxicities. “Central nervous system toxicities presented with symptoms of encephalopathy, but they’re usually reversible,” said Dr. Aldoss. “Flu-like symptoms are also common, and some patients experience hypogammaglobulinemia, elevated liver enzymes, and/or infections.”
According to Dr. Aldoss, future research should involve optimizing drug delivery and incorporating blinatumomab in the front-line setting. “Blinatumomab is an ideal drug to combine with other novel agents, but a better understanding of how ALL genetics and host immune profiles correlate with response is needed. The unique pattern of relapse and progression also requires further investigation,” he observed.
Finally, other targeted BiTEs may be active in other diseases, as well. CD33 is universally expressed on acute myeloid leukemia (AML) cells. Using AMG330, a CD3/CD33-bispecific antibody, preclinical studies have shown high potency and efficacy in destroying CD33-positive human AML cells.7 A phase I study of AMG 330 in subjects with relapsed/refractory AML is currently recruiting participants. ■
Disclosure: Dr. Aldoss is on the advisory board for Helocyte.
3. Goekbuget N, Dombret H, Bonifacio M, et al: BLAST: A confirmatory, single-arm, phase 2 study of blinatumomab, a bispecific T-cell engager antibody construct in patients with minimal residual disease B-precursor acute lymphoblastic leukemia. 2014 ASH Annual Meeting. Abstract 379. Presented December 8, 2014.
5. Stein AS, Topp MS, Kantarjian HM, et al: Treatment with anti-CD19 BiTE blinatumomab in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia post-allogeneic hematopoietic stem cell transplantation. 2015 ASH Annual Meeting. Abstract 861. Presented December 7, 2015.
6. Topp MS, Stelljes M, Zugmaier G, et al: Retreatment with blinatumomab after CD19-positive relapse: Experience from 3 trials in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia. 2015 European Hematology Association Congress. Abstract P165. Presented December 6, 2015.