Immunotherapies Open New Avenues in Relapsed/Refractory ALL

Up until recently, the 5-year survival rate for relapsed and refractory (R/R) acute lymphoblastic leukemia (ALL) was below 10%. New therapies, however, are starting to challenge that paradigm, and a remarkably difficult malignancy may be becoming at least somewhat more manageable.

Rebecca B. Klisovic, MD, of the Ohio State University Comprehensive Cancer Center in Columbus, spoke about some of the new R/R ALL options at the 11th Annual National Comprehensive Cancer Network (NCCN) Hematologic Malignancies Congress, held September 30–October 1 in New York. She pointed out that though 80% of adults with primary ALL will achieve a complete remission, most ultimately relapse, and 20% have resistant disease.

The new options in R/R ALL are immunotherapies, both monoclonal antibodies and the use of chimeric antigen receptor (CAR) T cells. The monoclonal antibodies have three primary targets in CD19, CD20, and CD22, and include unconjugated antibodies, antibody-drug conjugates, antibody-toxin conjugates, and bispecific T cell–engager antibodies (BiTEs).

Blinatumomab is a BiTE, targeting CD19 as well as CD3. Early work on the agent focused on conversion to minimal residual disease (MRD) status, Klisovic said. In the phase II GMALL study, 16 of 20 patients with MRD persistence or relapse after induction and consolidation therapy converted to MRD-negative status.

Specifically in R/R disease, a study including 189 patients had a 43% complete remission rate and a median relapse-free survival of 5.9 months with blinatumomab treatment. These results were published in Lancet Oncology in 2015.

Blinatumomab’s most common grade 3 or 4 adverse event is lymphopenia, occurring in 33% of patients in the Lancet Oncology study. Other common toxicities of any grade included fever, chills, headache, fatigue, hypogammaglobulinemia, and hypokalemia. “Cytokine release syndrome [CRS] has its greatest risk on the first day of the cycle, and then of course with any dose escalation,” Klisovic said. Pretreatment with steroids can reduce circulating disease burden, and treatment with dexamethasone during blinatumomab initiation and escalation can be effective as well.

Neurotoxicity was dose limiting with this drug, and can include encephalopathy, seizures, coordination and speech difficulties, confusion, and impaired cognition. “‘Not acting right’ is what I teach the fellows,” Klisovic said. It may be necessary to interrupt infusions for grade 3 neurotoxicity, and grade 4 likely requires permanent discontinuation.

Inotuzumab is another newly developed monoclonal antibody, conjugated to calicheamicin and targeting CD22. The phase III INO-VATE trial tested this drug in 326 relapsed ALL patients, compared with standard of care. An initial analysis of the first 218 patients randomized showed a remarkable complete remission rate of 80.7% with inotuzumab, compared with 29.4% with standard of care (P < .0001). The progression-free survival analysis of all 326 patients showed a significant improvement (P < .001), and though overall survival was longer with the study drug, the prespecified boundary for overall survival was not met, with a hazard ratio of 0.77 (97.5% CI, 0.58–1.03; P = .04).

There was more hepatic toxicity with inotuzumab, and Klisovic pointed out that veno-occlusive disease was found in 10 of 48 patients who proceeded with allogeneic stem cell transplant.

The other approach under investigation for R/R ALL involves CAR T cells. This involves reprogramming T cells to recognize and eliminate malignant cells. Klisovic said that in ALL this has mostly been studied only in small phase I trials so far, but remission rates seen in those trials have been remarkable. For example, one study published in 2014 in the New England Journal of Medicine showed a complete remission in 27 of 30 patients (90%) and a sustained remission involving event-free survival for at least 6 months in 67%.

CRS is the most common acute toxicity with this therapy. The most common initial symptoms include fever, tachycardia, and hypertension.

“Immunotherapies really do offer great promise in managing R/R ALL,” Klisovic said. Managing the unique toxicities to these agents remains an important point of focus, she noted, and support for clinical trials in this malignancy is crucial to move the field forward.