Long-Term Clinical Benefit Observed With KTE-X19 for Treatment of Relapsed/Refractory B-ALL

Heavily pretreated patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) who received a single infusion of the CAR T-cell therapy, KTE-X19 (Tecartus), experienced robust and durable responses, according to data presented virtually during the 2021 ASCO Annual Meeting.¹

At a median follow-up of 16.4 months (range, 10.3-22.1) in the phase 2 ZUMA-3 trial (NCT02614066), the complete response/complete response with incomplete blood count recovery (CR/CRi) rate was 70.9%, including a CR rate was 56.4%. Additionally, 31% of responding patients were in ongoing remission at data cutoff, without the need for subsequent allogeneic stem cell transplantation (ASCT) consolidation. Moreover, the median overall survival (OS) was 18.2 months for all patients treated on the study, and has not yet been reached in those who achieved a CR/CRi.

“The efficacy, rapid manufacturing, and manageable safety profile support the promising role of KTE-X19 to provide a long-term clinical benefit in adult patients with relapsed/refractory B-ALL,” Bijal Shah, MD, MS, an associate member in the Department of Malignant Hematology at Moffitt Cancer Center, said during aa presentation on the data.

Among adult patients with B-ALL, approximately 40% to 50% experience relapse following initial treatment, and prognoses remain poor.^2,3 For patients with relapsed/refractory B-ALL, the 1-year OS rate is 26% after first salvage therapy and continues to decrease with each subsequent line of therapy thereafter.⁴ Additionally, while novel agents, such as blinatumomab (Blincyto) and inotuzumab ozogamicin (Besponsa), have yielded positive outcomes in this patient population, median OS is still less than 8 months and is largely dependent on ASCT.^4-7

In order to address the unmet needs within this patient population, the phase 1/2 ZUMA-3 trial was conceived to examine KTE-X19, an autologous anti–CD-19 CAR T-cell therapy that was approved by the FDA in July 2020 for the treatment of patients with relapsed/refractory mantle cell lymphoma. Previously, the phase 1 ZUMA-3 trial demonstrated a manageable safety profile, with an overall CR/CRi rate of 83%. Moreover, the phase 1 portion of the study established the recommend phase 2 dose of KTE-X19 at 1x10⁶ CAR T cell/kg¹⁰.

The phase 2 portion of the ZUMA-3 trial included the largest adult-only population of patients with relapsed/refractory B-ALL to date.

In total, 71 adult patients were enrolled on the phase 2 portion of the ZUMA-3 study. Patients needed to be 18 years old or older with relapsed/refractory B-ALL and bone marrow blasts of greater than 5%. Additionally, patients who had received prior treatment with blinatumomab were able to enroll.

Patients underwent conditioning chemotherapy with fludarabine at a dose of 25 mg/m2 on days -4, -3, and -2 prior to infusion, as well as with cyclophosphamide at a dose of 900 mg/m2 on day -2 prior to infusion. Then, patients went on to receive the infusion of KTE-X19 at a dose of 1x10⁶ anti-CD19 CAR T cells/kg on day 0.

The primary end point for the study was CR/CRi by central assessment, with key secondary end points including minimal residual disease (MRD)–negativity rate, duration of response (DOR), relapse-free survival (RFS), OS, safety, and CAR T-cell levels in blood, and cytokine levels in serum.

Of the 71 patients enrolled on study, 57 went on to conditioning chemotherapy, and 55 went on to receive KTE-X19 infusion. The primary reasons for not proceeding to infusion included infection, thrombosis, and failing to meet eligibility. Moreover, safety and efficacy results were reported from the 55 patients who went on to receive infusion.

KTE-X19 was successfully manufactured for 92% of patients (n = 65/71). Moreover, the median time from leukapheresis to KTE-X19 manufacturing release was 13 days for patients in the United States, while it was 14.5 days for patients in Europe.

Among patients enrolled on the study, the median age was 40 years old (range, 19-84), and the majority were male (60%) with an ECOG performance status of 1 (71%). Additionally, 27% of patients were Philadelphia chromosome–positive and all had central nervous system–disease at baseline. Patients received a median of 2 prior therapies (range, 1-8) and 47% of patients had undergone 3 or more prior lines of therapy.

The majority of patients enrolled has relapsed on or were refractory to 2 or more prior systemic lines of treatment (78%), while 45% of patients had received prior treatment with blinatumomab, 22% received prior treatment with inotuzumab ozogamicin, and 42% had undergone prior ASCT. Moreover, the median rate of bone marrow blasts at screening was 65% (range, 5%-100%), while the median rate at preconditioning after bridging chemotherapy was 59% (range, 0%-98%).

For patients who achieved a CR/CRi, the median time to CR/CRi was 1.1 months (range, 0.85-2.99). Additionally, 10 patients in total, including 9 who had achieved a CR/Cri and 1 with blast-free hypoplastic or aplastic bone marrow, underwent ASCT at a median of 98 days (range, 60-207) following treatment with KTE-X19. Additionally, the minimal residual disease (MRD)-negativity rate was 97% in responders.

“Responses were largely consistent across subgroups, including those who were older, those who were more heavily pretreated, those who had undergone prior ASCT, … and those who were considered primary refractory,” Shah said. “The only group to show a lower response rate were those with a bone marrow blast burden greater than 75%.”

The median DOR was 12.8 months, with or without censoring patients at subsequent ASCT and as of data cutoff, 31% of the patients who achieved a CR or CRi had ongoing remissions without receiving subsequent ASCT.

Moreover, the median RFS was 11.6 months for patients who received KTE-X19, and 14.2 months for those who achieved a CR/CRi.

In terms of safety, the most common grade 3 or higher adverse effects (AEs) were anemia (49%) and pyrexia (36%). There were also 10 instances of grade 5 AEs reported, 4 of which were ALL; 2 were treatment-emergent from KTE-X19 and included brain herniation and septic shock; 3 occurred after initiation of another cancer treatment and included fungal pneumonia, sepsis, and respiratory failure; and 1 was pneumonia unrelated to treatment with KTE-X19.

There were not reported grade 5 events of cytokine release syndrome (CRS) or other neurological AEs. However, 24% of patients reported grade 3 or higher CRS, while 25% reported other grade 3 or higher neurological events. To treat these AEs, patients were given tocilizumab (Actemra; 80%), steroids (75%), and vasopressors (40%).

Higher levels of peak CAR T-cells were seen in patients with ongoing CR/CRi, followed by those who relapsed, and was lowest in those who did not achieve a CR or Cri. Moreover, levels were higher in patients who achieved CR/CRi and those who were MRD-negative. Peak CAR T-cell levels were also positively associated with grade 2 or higher CRS and grade 3 or higher neurological events. Moreover, the median time to peak CAR T-cells levels in the blood after infusion with KTE-X19 was 15 days (range, 7-32). In the 10 responders with evaluable samples at month 12, everyone had recovered peripheral B cells while 1 patients had detectable T cells.

References

1. Shah B, Ghobadi A, Oluwole O, et al. Phase 2 results of the ZUMA-3 study evaluating KTE-X19, an anti-CD19 chimeric antigen receptor T-cell therapy, in adult patients with relapsed/refractory B-cell acute lymphoblastic leukemia. J Clin Oncol. 2021;39(15):7002-7002. doi:10.1200/JCO.2021.39.15_suppl.7002

2. Paul S, Kantarjian H, Jabbour E, et al. Adult acute lymphoblastic leukemia. Mayo Clin Proc.2016;91(11):1645-1666. doi:10.1016/j.mayocp.2016.09.010.

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4. Topp M, Gökbuget N, Stein A, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet. 2015;16(1):P57-66. doi:10.1016/S1470-2045(14)71170-2

5. Kantarjian H, DeAngelo D, Stelljes M, et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N Engl J Med. 2016;375:740-753. doi:10.1056/NEJMoa1509277

6. Kantarjian H, DeAngelo D, 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

7. DeAngelo D, Stock W, Stein A, et al. Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. Blood Adv. 2017; 1(15):1167-1180. doi:10.1182/bloodadvances.2016001925.