Special Considerations Accompany Newer Agents in R/R B-Cell ALL

Emily Curran, MD

In the past 5 years, 3 new options have emerged to treat patients with relapsed/ refractory acute lymphoblastic leukemia (ALL), providing hope for patients with this disease but also raising clinical questions of how to choose among these agents and what is the best option for the patient at which time.¹

“I think that it’s an exciting time in ALL. We have a bunch of new treatments that work really well, and I think it’s a great problem to have—we have so many things to choose from that sometimes it can be difficult to choose,” commented Emily Curran, MD, in a presentation during the eighth annual Society of Hematologic Oncology meeting.

Curran, assistant professor, Department of Medicine, Section of Hematology & Oncology at the University of Cincinnati in Ohio, addressed considerations for the optimal setting for the use of blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and tisagenlecleucel (Kymriah) for patients with relapsed/refractory ALL and how to choose among these options.

Efficacy of Newer Treatments

Blinatumomab is a bispecific T-cell engager directed against CD19 and CD3 that first received FDA approval for the treatment of patients with Philadelphia chromosome (Ph)– negative relapsed/refractory B-cell precursor ALL in December 2014. The agent is also indicated for the treatment of patients with Ph-positive disease as well as for both adults and children who are in remission but still have minimal residual disease (MRD).

Approval for blinatumomab was expanded following the results of the open-label, multicenter phase 3 TOWER trial (NCT02013167). The study randomized 405 adult patients with heavily pretreated B-cell precursor ALL 2:1 to either blinatumomab or standard-of-care chemotherapy.²

Within 12 weeks of starting treatment, the rate of complete response (CR) or CR with partial hematologic recovery was 43.9% with blinatu-momab compared with 24.6% with chemotherapy (P < .001). Additionally, of these responders, 76% in the blinatumomab arm had MRD negativity compared with 48% in the chemotherapy arm.

The median overall survival (OS) was 7.7 months with blinatumomab versus 4.0 months with chemotherapy (HR, 0.71; 95% CI, 0.55-0.93; P = .01). The median duration of remission was 7.3 months versus 4.6 months with blinatumomab and chemotherapy, respectively.

Inotuzumab ozogamicin is an anti-CD22 antibody conjugated to calicheamicin that was approved for the treatment of adult patients with relapsed/refractory B-cell precursor ALL by the FDA in August 2017. The approval was based on findings from the open-label, randomized, multicenter phase 3 INO-VATE ALL trial (NCT01564784). In the trial, 326 patients were randomized to either inotuzumab ozogamicin treatment or standard intensive chemotherapy, but only 218 patients were included in the intention-to-treat (ITT) analysis. All patients had CD22-positive disease and were enrolled regardless of Ph status.³

Within the ITT population, the rate of CR/ CRi (CR with incomplete hematologic recovery) was 80.7% with inotuzumab ozogamicin versus 29.4% with standard chemotherapy (P < .001). The median progression-free survival was 5.0 months in the inotuzumab ozogamicin arm compared with 1.8 months in the standard-therapy arm (HR, 0.45; 97.5% CI, 0.34-0.61; P < .001). The median OS was 7.7 months and 6.7 months in the investigational and control arms, respectively (HR, 0.77; 97.5% CI, 0.58-1.03; P = .04).

Chimeric antigen receptor (CAR) T-cell therapy is a newer approach in the treatment of hematologic malignancies. Tisagenlecleucel, a CD19- directed CAR T-cell therapy, was the first CAR T-cell product approved for use by the FDA and was first indicated for the treatment of patients up to 25 years old with B-cell precursor ALL that is refractory or in second or later relapse.⁴

This indication was based on data from the single-cohort phase 2 ELIANA trial (NCT02435849) that included 75 pediatric and young-adult patients with CD19-positive relapsed/refractory B-cell ALL. At 3 months, the overall remission rate was 81%, consisting of all CRs or CRis, and negative MRD status was achieved in all patients who had a response. The OS rate was 90% at 6 months and 76% at 1 year.⁵

Overall, CD19-directed CAR T-cell therapies have shown significant response rates in treating ALL across various trials. An analysis suggested that CAR T-cell products that used a 4-1BB costimulatory domain, as in tisagenlecleucel, may have better persistence of treatment and lead to longer disease-free intervals than those that used a CD28 costimulatory domain. For example, the CR rate in studies with CD28 signaling domains ranged from 67% to 83% compared with 81% to 93% with 4-1BB signaling domains.⁶

However, CAR T-cell therapy is associated with significant cytokine release syndrome (CRS) and neurotoxicity. To address the risk of CRS, the FDA approved the use of tocilizumab (Actemra) concurrently with the initial tisagenlecleucel approval.⁴

In the ELIANA trial, for example, the rate of CRS was 77%, with 47% patients being admitted to the intensive care unit for treatment of CRS. Thirty-seven percent of patients received treatment with tocilizumab. Additionally, neurotoxicity was seen in 40% of patients; the majority of these cases of neurotoxicity overlapped with CRS.⁵

Comparing the Options to Decide the Best Approach for Patients

Choosing among the 3 options comes down to a number of factors involving patient and disease characteristics. For example, the approval language for tisagenlecleucel states that it is indicated for patients younger than 25 years, whereas inotuzumab ozogamicin is indicated only for patients 18 years or older.

Rates of CR and OS were highest with CAR T-cell therapy when comparing the 3 agents, but the rates of MRD negativity achieved were similar across the studies. Patients treated with blinatumomab who had a high disease burden (in terms of ≥ 50% blasts) showed lower response rates and worse quality-of-life scores than those with a lower burden of disease.2 On the other hand, inotuzumab showed benefit in patients regardless of disease burden.

“I think it’s important to at least keep this in mind when choosing an up-front therapy. If somebody has a higher disease burden, you may want to consider inotuzumab as opposed to blinatumomab or perhaps even as opposed to CAR T-cell therapy,” Curran said.

Also, toxicities are generally higher among patients with a high disease burden, Curran pointed out. For example, with CAR T-cell therapy, patients with a high disease burden had a higher incidence of severe CRS, at 41% compared with 5% in patients with a lower disease burden, and of neurotoxicity, at 59% versus 14%, respectively. Blinatumomab has a similar toxicity profile, but Curran said that whether disease burden affects toxicity with this treatment is less clear.

Inotuzumab ozogamicin has a different toxicity profile compared with the other 2 agents and is associated with more veno-occlusive disease. This is thought to be associated with stem cell transplant and the use of a dual alkylator conditioning regimen. “In patients who are being considered for transplant…it is an important consideration,” Curran noted.

Long-term remission may still require undergoing stem cell transplant, especially for patients treated with inotuzumab ozogamicin. This treatment was able to increase the number of patients who went on to receive transplant compared with standard therapy, but after transplant, the survival was the same in both arms.³ Alternatively, blinatumomab showed long-term responses even in patients who did not undergo transplant.²

“Keep in mind…that both blinatumomab and CAR T-cell therapy…require the use of functioning T cells for optimal response,” Curran said. Additionally, she pointed out that CAR T-cell therapy is able to cross the blood-brain barrier, unlike the other treatments, making it a more effective choice in the case of central nervous system disease.

Finally, the method and timing of administration are important to consider in accordance with the patient’s wishes. Curran noted that with blinatumomab, an inpatient stay is not required, but a patient will be required to carry a pump. CAR T-cell therapy is usually given in an inpatient setting, though some centers are moving toward an outpatient setting, but since manufacturing of the CAR T cells is required, a delay in treatment may exist with this approach. “In someone who needs treatment right away, that might not be the best choice,” she said.

Curran noted that these suggestions may continue to change as more data and agents become available and more is learned about predicting for response or relapse in patients and providing them with the optimal treatment.

_References:

_{1. Curran E. In relapsed B-ALL, how should we best sequence the new targeted agents? Presented at: 2020 Society of Hematologic Oncology Annual Meeting; September 9-12, 2020.}

_{2. Kantarjian H, Stein A, Gökbuget N, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836-847. doi:10.1056/NEJMoa1609783}

_{3. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375(8):740-753. doi:10.1056/NEJMoa1509277}

_{4. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. News release. FDA. Updated September 7, 2017. Accessed September 9, 2020. https://bit.ly/2FgpozU}

_{5. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi:10.1056/NEJMoa1709866}

_{6. Frey NV. Chimeric antigen receptor T cells for acute lymphoblastic leukemia. Am J Hematol. 2019;94(S1):S24-S27. doi:10.1002/ajh.25442}