Treatment Sequencing Could Change With Complementary Combinations and CAR T Options in B-ALL

Elias Jabbour, MD

Significant progress with rapidly evolving therapies, including blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and chimeric antigen receptor (CAR) T-cell therapy, has been made to extend the median overall survival (OS) and improve outcomes for patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). Antibody-based therapies and CAR T-cell therapies are not mutually exclusive, according to Elias Jabbour, MD, who added that competitive options have the potential to be complementary if sequenced earlier.

“Until recently, when somebody with ALL relapsed, the outcomes were bad and we didn’t have anything [available to treat them],” said Jabbour, a professor of medicine in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, in an interview with OncLive^®. Jabbour previewed his presentation on the practice-changing updates in relapsed/refractory B-ALL.

“Over the past few years, we’ve [had] several options [become] available to our patients, [including] the bispecific engagers, antibody-drug conjugates [ADCs], and CAR T-cell therapies, first for pediatric and [adolescent and] young adult [AYA] patients and now for adult patients. Each [therapy] has shown a benefit when compared with standard of care. The question is: How do we optimize the [options] to improve outcomes in ALL?” Jabbour asked.

Although not yet backed by level 1 evidence, a potentially promising therapeutic sequencing strategy could incorporate blinatumomab in combination with inotuzumab ozogamicin as frontline therapy followed by consolidative CAR T-cell therapy, Jabbour explained. He added that this strategy could begin to phase out the use of allogeneic stem cell transplant and chemotherapy in B-ALL because these approaches may not be optimal following CAR T-cell therapy.

“Each [option] alone is not great enough. The value of treatment can be further improved,” Jabbour said. “This way we can offer these treatments, which are expensive and not [widely] available, in the most optimal way. We can improve the cure rate instead of giving every agent alone with minimal or acceptable benefit.”

Milestones Extend OS Across ALL

Over several decades, the 5-year OS rate for patients with ALL has increased from 26% between 1984 and 1989 to 59% between 2010 and 2019. Reasons for this success include the addition of TKIs like ponatinib (Iclusig) with or without blinatumomab to chemotherapy-based regimens in patients with Philadelphia chromosome–positive ALL, the addition of rituximab (Rituxan) to chemotherapy in Burkitt and pre–B-ALL, and the use of CAR T-cell therapy in B-ALL. Additionally, although still being fleshed out, the importance of minimal residual disease (MRD) as a predictive marker for progression has become understood in recent years.

Blinatumomab and Inotuzumab Ozogamicin Make a Splash in Relapsed/Refractory B-ALL

In 2017, the FDA granted a full approval to the monoclonal antibody blinatumomab for the treatment of adult and pediatric patients with relapsed/refractory B-cell precursor ALL.¹ The approval was based on findings from the phase 3 TOWER trial (NCT02013167), in which blinatumomab elicited a 44% complete remission (CR) with full, partial, or incomplete hematologic recovery (CRi) rate vs 25% with standard of care chemotherapy (P < .001).² The median OS was 7.7 vs 4 months, respectively (HR, 0.71; 95% CI, 0.55-0.93; P = .01).

Another phase 3 study (NCT02101853) evaluated blinatumomab vs chemotherapy in children and AYA patients with B-ALL in first relapse.³ The 2-year disease-free survival rate was 54.4% with blinatumomab vs 39% with chemotherapy (HR, 0.70; 95% CI, 0.47-1.03; P = .03). The 2-year OS rates were 71.3% vs 58.4%, respectively (HR, 0.62; 95% CI, 0.39-0.98; P = .02).

Also in 2017, the ADC inotuzumab ozogamicin was approved by the FDA for the treatment of adults with relapsed/ refractory B-cell precursor ALL based on findings from the phase 3 INO-VATE trial (NCT01564784).⁴ Updated results showed a 73.8% CR/CRi rate with inotuzumab ozogamicin vs 30.9% with standard-of-care chemotherapy in this patient population (P < .0001).⁵

Combination Regimens Spell Out Additional Success

In an ongoing phase 1/2 study (NCT01371630), inotuzumab ozogamicin in combination with low-intensity mini–hyper-CVD (mini-HVCD), a chemotherapy regimen consisting of cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m² for 4 doses, demonstrated encouraging activity in patients with relapsed/ refractory Philadelphia chromosome–negative ALL.⁶

Long-term follow-up data from the study showed an overall response rate of 80% with inotuzumab ozogamicin plus miniHVCD, with a complete response rate of 57% among 96 patients treated.⁷ The MRD negativity rate among responders was 83%.

To further expand this regimen, another study evaluated sequential inotuzumab ozogamicin with mini-HVCD with or without blinatumomab as salvage therapy for patients with ALL in first relapse.⁸ The results showed a median OS of 16.5 months with the combination as first-line salvage therapy and 5.8 months as second-line or later salvage therapy, indicating that salvage status affects OS, Jabbour said.

CAR T-cell Therapy Enters the Relapsed/Refractory Arena

In 2017, the CAR T-cell therapy tisagenlecleucel (Kymriah) became the first gene therapy to be approved in the United States.⁹ The regulatory decision made the therapy available for use in pediatric and AYA patients with relapsed/refractory B-ALL.

Updated findings from the phase 2 ELIANA trial (NCT02435849) demonstrated a 24-month OS rate of 66% with tisagenlecleucel in this patient population.¹⁰ On October 1 another CAR T-cell product, brexucabtagene autoleucel (brexu-cel; Tecartus) was approved by the FDA for use in adult patients with relapsed/refractory B-ALL.¹¹

adult patients with relapsed/refractory B-ALL.11 The decision was based on findings from the phase 1/2 ZUMA-3 trial (NCT02614066), in which a single infusion of brexu-cel elicited a high response rate consisting of durable responses in patients with heavily pretreated relapsed/refractory B-ALL.^12-13

Of 54 patients in the efficacy population, 64.8% (95% CI, 51%-77%) of patients who received brexu-cel had a CR/CRi (Table¹³). Over half of patients (51.9%) obtained a CR. Moreover, the median duration of remission (DOR) was 13.6 months (95% CI, 9.4-not estimable [NE]). The median DOR for those who achieved CR was not reached (95% CI, 9.6-NE) and the median DOR for those who achieved CRi was 8.7 months (95% CI, 1.0-NE).¹³

In previously reported data, nearly all responders (97%) had MRD negativity after treatment with brexu-cel. Regarding safety, grade 3 or higher cytokine release syndrome occurred in 24% of patients who received brexucel. Grade 3 or higher neurologic toxicities occurred in 25% of patients.¹²

“We just started the journey with CAR T-cell therapy. There is no question that our management of toxicity will improve. We will gain more expertise, so what we see today may not be the case in 5 to 6 years,” Jabbour said.

Jabbour also highlighted that accessibility remains another challenge of CAR T-cell therapy that needs to be overcome. “The accessibility [of CAR T-cell therapy] is a problem today, but ALL is [also] a rare disease. We can only become experts if we have patients,” Jabbour added.

“I’d like to know where CAR T-cell therapy benefits patients most. Activity has been shown across refractory populations, but we know that outcomes can be better in patients with minimal to no disease. That is where I see a role for CAR T-cell therapy. I try to cytoreduce and give CAR T-cell therapy after to offer the best outcomes,” Jabbour said.

Capitalizing upon the success demonstrated with CAR T-cell therapy, research efforts are under way to evaluate improved CAR T-cell therapy designs, dual targeting CAR T-cell therapies, allogeneic products, and fractionated CAR T-cell therapies, Jabbour explained. Notably, CAR T-cell therapy could largely replace the need for allogeneic stem cell transplant for patients with B-ALL who have MRD in first remission.

“We are in the best [era because] we have the tools to cure ALL. Everything is ready in our hands. The future involves using less chemotherapy but more targeted approaches. Some of [the targeted options] are in the refractory field right now, but they are moving rapidly to the frontline setting to change the field,” Jabbour concluded.

References

1. FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome-positive B cell. FDA. Updated July 12, 2017. Accessed October 20, 2021. bit.ly/3lYi0w7
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. Brown PA, Ji L, Xu X, et al. Effect of postreinduction therapy consolidation with blinatumomab vs chemotherapy on disease-free survival in children, adolescents, and young adults with first relapse of B-cell acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 2021;325(9):833-842. doi:10.1001/jama.2021.0669
4. FDA approves inotuzumab ozogamicin for relapsed or refractory B-cell precursor ALL. FDA. August 17, 2017. Accessed October 20, 2021. https://bit.ly/3vvLJ2p
5. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: final report and long-term survival follow-up from the randomized, phase 3 INO-VATE study. Cancer. 2019;125(14):2474-2487. doi:10.1002/cncr.32116
6. Jabbour E, Ravandi F, Kebriaei P, et al. Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini-hyper-CVD for patients with relapsed or refractory Philadelphia chromosome–negative acute lymphoblastic leukemia: a phase 2 clinical trial. JAMA Oncol. 2018;4(2):230-234. doi:10.1001/jamaoncol.2017.2380
7. Jabbour E, Sasaki K, Short NJ, et al. Long-term follow-up of salvage therapy using a combination of inotuzumab ozogamicin and mini-hyper-CVD with or without blinatumomab in relapsed/refractory Philadelphia chromosome-negative acute lymphoblastic leukemia. Cancer. 2021;127(12):2025-2038. doi:10.1002/cncr.33469
8. Rafei H, Kantarjian HM, Sasaki K, et al. Sequential combination of inotuzumab ozogamicin (InO) with low-intensity chemotherapy (mini-hyper-CVD) with or without blinatumomab (Blina) as salvage therapy for patients (Pts) with acute lymphoblastic leukemia (ALL) in first relapse. Blood. 2020;136(suppl 1):36-38. doi:10.1182/ blood-2020-143386
9. FDA approval brings first gene therapy to the United States. News release. FDA. Updated March 26, 2018. Accessed October 20, 2021. bit.ly/3B1HpsV
10. Grupp S, Maude S, Baruchel A, et al. Tisagenlecleucel appears effective and safe in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia with high-risk cytogenetic abnormalities. Presented at: European Hematology Association Congress 2019; June 13-16, 2019. Abstract S1618. Accessed October 20, 2021. bit.ly/3E1OQCc
11. FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. October 1, 2021. Accessed October 20, 2021. bit. ly/2Z9Xekg
12. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. doi:10.1016/S0140- 6736(21)01222-8
13. Tecartus. Prescribing information. Kite Pharma Inc; 2021. Accessed October 22, 2021. https://www.fda.gov/media/140409/download