New Therapeutic Agents for the Treatment of B-Cell Acute Lymphocytic Leukemia
San Francisco, CA—Therapies targeting immune responses against solid tumors have led to dramatic improvements in outcomes, but the role for immunotherapy in the treatment of acute leukemia is still being defined.
At the 2017 NCCN Hematologic Malignancies Congress, David G. Maloney, MD, PhD, Medical Director, Cellular Immunotherapy, Fred Hutchinson Cancer Research Center, Seattle, WA, discussed the latest immunotherapies for the treatment of acute lymphocytic leukemia (ALL), including chimeric antigen receptor (CAR) T-cell therapy, which demonstrated complete response in 94% of heavily pretreated patients in one clinical trial.
Improved sequencing and combinations of immunotherapies will likely reduce the need for allogeneic hematopoietic stem-cell transplant, said Dr Maloney.
Rituximab for CD20-Positive Disease
Rituximab (Rituxan), an anti-CD20 monoclonal antibody, was approved 20 years ago by the FDA for CD20-positive lymphocytes, but not for ALL. Recently, a randomized clinical trial showed that compared with standard-of-care chemotherapy, the addition of rituximab to chemotherapy improved outcomes in patients with CD20-positive, Philadelphia chromosome–negative ALL.1
The results showed an increase in the 2-year event-free survival from 52% to 65% (P = .04) and a decreased relapse rate. Furthermore, a trend for improved overall survival and for more rapid clearing of minimal residual disease compared with chemotherapy alone was also seen. In addition, there were fewer allergic reactions to asparaginase with rituximab versus chemotherapy.
“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.
In August 2017, the FDA approved inotuzumab ozogamicin (Besponsa), a CD22-directed antibody drug conjugate for the treatment of patients with relapsed or refractory B-cell precursor ALL. This antibody drug conjugate is present in all patients with mature B-cell ALL and in >90% of patients with precursor B-cell ALL.
The approval was based on the phase 3 clinical trial of 326 adults with relapsed or refractory ALL that showed that patients who received inotuzumab ozogamicin had a significantly higher rate of complete response compared with patients who received standard-of-care chemotherapy (80.7% vs 29.4%, respectively; P <.001). Furthermore, complete responses occurred regardless of the duration of the first remission, patient age, and the phase of salvage treatment.2
“All groups retained statistical significance in favor of inotuzumab ozogamicin,” said Dr Maloney, who noted that even patients who did not respond to stem-cell transplantation had high rates of complete remission.
However, despite the high rates of complete remission, long-term follow-up was described as “somewhat disappointing.” At 10 to 12 months, only a small proportion 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 (Blincyto), a bispecific monoclonal antibody combining anti-CD19 with anti-CD3, was approved by the FDA in July 2017 for the treatment of patients with relapsed or refractory B-cell precursor ALL. In the phase 3 clinical trial of adults with relapsed or refractory B-cell precursor ALL, treatment with blinatumomab resulted in significantly longer overall survival than treatment with chemotherapy (7.7 months vs 4.0 months, respectively; P = .01).3
In addition, remission rates within 12 weeks after treatment initiation were significantly higher in the blinatumomab group than in the standard-of-care chemotherapy group, and treatment with blinatumomab resulted in a higher rate of event-free survival at 6 months than with chemotherapy (31% vs 12%, respectively; P <.001).
However, although there is a clear overall benefit with blinatumomab compared with conventional therapy, the response rates are moderate, and blinatumomab is still not curing the majority of patients with this disease, Dr Maloney said. Moreover, the 4-week continuous infusion can be cumbersome for patients, and blinatumomab therapy is associated with significant toxicities, he added.
CAR T-Cell Therapy for B-Cell ALL
Modification of T-cells using CAR T-cell therapy is one of the hottest topics in oncology and has already led to a multitude of new therapies, according to Dr Maloney. The key is the target of the CAR T-cell therapy.
At the Fred Hutchinson Cancer Research Center, Dr Maloney and colleagues have treated more than 200 patients based on protocol 2639, which is evaluating CD19 CAR T-cell therapy manufactured from a mix of CD8-positive and CD4-positive–derived T-cell subsets.4 The study included 36 adults with B-cell ALL who have received lympho-depleting chemotherapy.4
These were heavily pretreated patients, many of whom would not qualify for further clinical trials, reported Dr Maloney. However, despite the advanced stage of their disease, 94% of patients had a complete response, and deep sequencing of the immunoglobulin heavy locus genes showed that the index clone was undetectable in 65% of patients.
Dr Maloney described the investigational CD19 CAR T-cell drug as “remarkably potent,” but cautioned that CAR T-cell therapy should be administered in centers with experience with this type of therapy, because of the serious side effects, including cytokine release syndrome and neurotoxicity associated with CAR T-cell treatment.
- Maury S, Chevret S, Thomas X, et al; for GRAALL. Rituximab in B-lineage adult acute lymphoblastic leukemia. N Engl J Med. 2016;375:1044-1053.
- Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740-753.
- Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836-847.
- Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123-2138.