Tisagenlecleucel versus historical standard therapies for pediatric relapsed/refractory acute lymphoblastic leukemia

Pediatric acute lymphoblastic leukemia (ALL) is rare, with an annual incidence of approximately 3.4–4.0 cases per 100,000 children [1,2]. However, despite its rarity, ALL is the most common form of childhood cancer [1,2]. In the USA, there are over 3000 new cases of ALL diagnosed in children and adolescents each year [2].

Multi-agent chemotherapy forms the backbone of current ALL treatment. With such treatments, prognosis for ALL is good; however, 15–20% of children with ALL will eventually relapse [3]. Although 30–85% of children with relapsed ALL can achieve a second complete remission (CR) with intensive combination chemotherapy regimens and allogeneic hematopoietic stem cell transplantation (allo-SCT), most children will not survive despite these aggressive approaches [4–8]. Recent data from the Children's Oncology Group show that 5-year survival rates (± standard error) for relapsed/refractory (r/r) B-cell ALL, T-cell ALL and infant ALL were 52 ± 1%, 33 ± 3% and 19 ± 4%, respectively [9]. Based on data from one of the leading international pediatric study groups, Berlin-Frankfurt-Münster, four different risk groups can be identified (S1, S2, S3 and S4) according to the site of relapse, time from diagnosis to relapse and immune phenotype [3]. Among children in the S3 and S4 risk groups, relapsed ALL following chemotherapy and SCT is associated with extremely poor overall survival (OS), with a 5-year OS of <5% (following chemotherapy) and 30% (S3) and 25% (S4) with allo-SCT showing the importance of novel salvage treatments for this disease [3].

Several therapies have been approved for the treatment of pediatric and young adult patients with relapsed or refractory ALL since 2000. Clofarabine is a purine nucleoside metabolic inhibitor that induces programmed cell death by inhibiting DNA synthesis and DNA chain elongation/repair [10]. In 2003, clofarabine was approved in the US and European Union for treatment of pediatric and young adult patients with r/r ALL after ≥2 prior regimens [10,11]. Phase II study in children and young adults with r/r ALL treated with clofarabine monotherapy reported CR rate (CR or CRp: a CR with or without platelet recovery) of 20% and median OS of 13 weeks; the most common grade 3–5 adverse events (AEs) were febrile neutropenia (49%), anorexia (20%), hypotension (18%), nausea (16%) and pyrexia (15%) [12,13].

More recently, blinatumomab, designated by the US FDA as a breakthrough therapy, was approved for the treatment of r/r adult patients (18 years and older) with B-cell precursor ALL in 2014 and later on for pediatrics in 2016 [14,15]. Blinatumomab is a bispecific CD19-directed CD3 T-cell engager (BiTE) antibody, which activates previously unstimulated T cells and induces redirected lysis of CD19-positive cells [14,16]. In a pivotal Phashe I/II study (MT103-205) of blinatumomab in pediatric patients with r/r ALL, 39% of patients achieved CR within two treatment cycles (M1 [<5% blasts in bone marrow] with full recovery of peripheral blood counts = 17% [12/70]; M1 with incomplete recovery of peripheral blood counts = 16% [11/70]); M1 without full or incomplete recovery of peripheral blood counts = 6% [4/70]); the median OS was 7.5 months [17]. Among these patients, the most common grade 3–5 AEs were anemia (36%), thrombocytopenia (21%), febrile neutropenia (17%), hypokalemia (17%) and neutropenia (17%); 7% experienced fatal adverse events [17]. Same as clofarabine and other salvage chemotherapies, blinatumomab treatments are often used as ‘bridges’ to SCT in patients with relapsed disease [12,17,18].

Despite improvement in treatment, pediatric and young adult patients with r/r ALL still have a dismal prognosis and face imminent death: median OS with newly approved therapies is approximately 3–8 months [12,17], and the majority of children with r/r ALL still do not survive the disease. Maintaining a remission in previously relapsed patients is difficult, and the prognosis of patients with r/r disease remains poor. The 5-year overall survival in children receiving allo-SCT in ≥ third remission is ∼30%. Only 17% of patients will receive a second SCT with a 3-year OS of 32% 5 year and 5-year OS of 22%. There remains an urgent unmet need for an effective treatment that offers improved survival independent of eligibility for SCT, delivers higher rates of hematologic CR rates and improves quality of life (QoL), with a lifetime benefit.

Tisagenlecleucel is the first chimeric antigen receptor (CAR)-T cell therapy approved in the US, European Union, Canada, Switzerland, Australia and Japan for the treatment of patients up to 25 years old with r/r B-cell ALL [19–23]. In the pivotal, Phase II, single-cohort, 25-center global study, ELIANA (NCT02435849), a single infusion of tisagenlecleucel provided durable remission with long-term persistence of tisagenlecleucel and transient high-grade toxic effects in pediatric and young adult patients with r/r B-cell ALL. The CR rate (defined as proportion of patients with best overall disease response of CR or CRi (incomplete hematologic recovery) within 3 months was 82%, and all patients who had CR were found to be negative for minimal residual disease (MRD; MRD-negative defined as <0.01% as assessed by flow cytometry). The median duration of remission was not reached with median follow-up 9.1 months. Rates of OS were 90% (95% CI, 81%–95%) at 6 months and 66% (95% CI: 54%–76%) at 24 months [24]. In addition, clinically meaningful improvements in patient-reported QoL were observed as soon as 1–3 months after tisagenlecleucel infusion (beyond the period of acute toxicities) and persist for 12 months [25]. A total of 88% of patients had grade 3 or 4 AEs, mostly within 8 weeks after infusion (≤8 weeks, 83%; >8 weeks to 1 year, 44%); 73% of patients had grade 3 or 4 AEs suspected to be related to tisagenlecleucel (≤8 weeks, 69%; >8 weeks to 1 year, 17%). Select AEs within 8 weeks after infusion occurred in 89% of patients and included cytokine release syndrome (CRS; 77%), infections (43%), neurologic events (40%), cytopenias not resolved by day 28 (37%), febrile neutropenia (35%) and tumor lysis syndrome. Of note, major concern for AE is CRS, neurologic event and B-cell aplasia. All patients with a response to treatment had B-cell aplasia, and most patients in the study received immunoglobulin replacement in accordance with local practice [24]. There is no AE post-tisagenlecleucel infusion leading to study discontinuation.

No randomized head-to-head trials have compared tisagenlecleucel with other salvage therapies (clofarabine, other chemotherapy regimens or blinatumomab). Absent head-to-head trials, matching-adjusted indirect comparison (MAIC) is a credible and widely used method for comparing treatment outcomes. MAIC analyses use individual patient data from trial(s) of one treatment to match the baseline summary statistics reported from trial(s) of a comparator [26]. After matching, treatment outcomes are compared across balanced trial populations using an approach similar to propensity score weighting [26]. It is one of the population-adjusted indirect comparison approaches recognized by the United Kingdom's National Institute for Health and Care Excellence and is well accepted across various health technology assessment (HTA) bodies [27,28]. There are some known limitations to MAIC analyses that can result from unobserved cross-trial differences or the inability to match all outcome definitions or inclusion/exclusion criteria [26]. The objective of this study is to compare the treatment effects of tisagenlecleucel with SOC regimens using MAIC, adjusting for heterogeneity in baseline characteristics between study populations.

Results of the global, pivotal Phase II ELIANA study of tisagenlecleucel in pediatric and young adult r/r B-cell ALL showed that tisagenlecleucel provided durable clinical remission and prolonged survival with a manageable safety profile [24]. However, absent head-to-head randomized trials, the magnitude of benefit over SOC regimens is unknown. We conducted a systematic literature review to identify the most relevant comparator treatments for tisagenlecleucel in this patient population, followed by MAIC to indirectly compare outcomes between regimens. All adjustment scenarios showed that tisagenlecleucel was associated with large benefit for pediatric and young adult patients with r/r ALL versus blinatumomab, CEC combination therapy, clofarabine monotherapy, salvage-1 and salvage-2 with regard to OS and CR rates. After adjustment, patients who received tisagenlecleucel were significantly more likely to experience CR and were estimated to be more than twice as likely to survive the first year.

Like other MAIC analyses, these analyses are limited by various assumptions inherent to the methodology. The MAIC analysis was conducted under the assumption that adjusting for patient baseline characteristics was sufficient to explain all differences in trial outcomes, that all important patient characteristics were reported and adjusted for, and that there were no subgroup effects or treatment effect modifiers. Any structural differences between studies remain unadjusted for. Second, eighteen (18.6%) out of 97 patients enrolled in ELIANA trial were not able to receive tisagenlecleucel, due to manufacture issue, dealth or adverse event before infusion. The added benefit using OS from enrollment (intent to treat [ITT] analysis) will be less, comparing tisagenlecleucel versus historical data. However, with improvement in manufacture process and expansion of global manufacture footprint overtime, the number of patients not able to receive tisagenlecleucel will continue to decrease in the real world. The ITT analysis based on trial data will likely underestimate the benefit of tisagenleceleucel in the real-world setting. Third, it was not possible to adjust for patients with T-cell ALL in the comparisons of tisagenlecleucel with CEC and salvage-1 because ELIANA did not include patients with T-cell ALL; the percentage of patients with T-cell ALL was 32% in one of the CEC trials and was 33% in the salvage-1 trial. The percentage of patients with T-cell ALL in the other studies were ≤21%. The comparison result with CEC and salvage therapy should be interpreted with caution. Furthermore, due to the lack of reference arms in the studies involved, it was not possible to conduct anchored comparisons or test for residual confounders. Last, literature review end date is March 2018. Any relevant comparator with publication since 2018 would not be included in this analysis.

Despite these limitations, given the magnitude of the clinically meaningful differences observed, these analyses likely are the best available evidence on the comparative efficacy of treatments in r/r pediatric and young adult patients with ALL. All studies used in this analysis, and almost all studies identified in the systematic literature review, are single arm. Consequently, a network meta-analysis approach is not possible, and statistical techniques such as MAIC are the most robust method for estimating relative efficacy. Obtaining reliable estimates of relative efficacy is a crucial step in supporting comparative research and health economic evaluations. To our knowledge, this is the first analysis built upon systematic literature review that estimates the relative efficacy of treatments in pediatric and young adult patients with r/r ALL in the post-CAR-T approval time period.

In summary, this study shows that tisagenlecleucel is associated with substantial clinical benefit over SOC regimens for pediatric and young adult patients with r/r ALL. Given the magnitude of disparities among treatment outcomes, it is highly unlikely that any residual confounders are responsible for the differences in efficacy.

This analysis used MAIC methodology to indirectly compare efficacy outcomes between tisagenlecleucel and SOC regimens, including blinatumomab, clofarabine monotherapy, CEC and salvage chemotherapy/treatment, as treatment for pediatric and young adult patients with r/r ALL. After adjusting for cross-study differences, tisagenlecleucel was associated with significantly longer OS and significantly higher CR rates compared with SOC regimens, with substantial magnitudes of improvement before and after MAIC. Real-world registry studies are warranted to confirm the magnitude of tisagenlecleucel benefit versus other treatments.

All authors were involved in the conception and design, or analysis and interpretation of the data; Q Ma was involved in the drafting of the paper; all authors were involved in revising the manuscript critically for intellectual content and gave final approval of the version to be published. All authors agree to be accountable for all aspects of the work.

This study and medical writing assistance were funded by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. The sponsor participated in the conception and design, or analysis and interpretation of the data; the drafting of the paper or revising it critically for intellectual content; and the final approval of the version to be published. Q Ma, J Zhang and AC Agostinho are employees and stockholders of Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. E O'Brien is an employee of Evidera, San Francisco, CA, USA and AL Martin is an employee of Evidera, Waltham, MA, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Editorial assistance was provided by S Lim of C4 MedSolutions, LLC (Yardley, PA, USA), a CHC Group company, and was funded by Novartis Pharmaceuticals Corporation. The authors thank M Rael and J Lee of Evidera, San Francisco, CA, USA for statistical support.

This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/