Sustained Benefit of Blinatumomab in Infants With KMT2A-Rearranged ALL: Long-Term Outcomes, Toxicity, and Pharmacokinetics

Abstract

KMT2A-rearranged infant ALL (KMT2A-r ALL) has a poor prognosis. Adding blinatumomab, a bispecific T-cell engager targeting CD19, to standard chemotherapy for infants with KMT2A-r ALL improved short-term outcomes. Here, we present long-term results, toxicity, and pharmacokinetics of blinatumomab from this study. Thirty infants received Interfant-06 protocol chemotherapy with one additional postinduction blinatumomab course. Disease-free survival (DFS) and overall survival (OS) were compared with a historical Interfant-06–selected cohort without blinatumomab. Infection and administration of intravenous immunoglobulin (IVIg) and granulocyte-colony stimulating factor (G-CSF) were documented. Blinatumomab's steady-state concentration (Css) and clearance (CL) were analyzed. The median follow-up was 4.2 years (range, 3.2-6.0). Blinatumomab significantly improved outcomes compared with controls, with a 4-year DFS of 83.3% versus 44.0% and a 4-year OS of 93.3% versus 60.2%. No infection-related fatality occurred postinduction, in contrast to 4% in Interfant-06. IVIg was administered in 19 (63%) patients, and G-CSF in five (17%). The mean Css of blinatumomab was 706 ± 194 pg/mL/d, and the median CL was 0.89 L/h/m² (range, 0.57-2.66). Adding blinatumomab to standard treatment for infants with KMT2A-r ALL resulted in sustained improvement in outcome. Pharmacokinetics were comparable across pediatric age groups. The benefit of blinatumomab in frontline therapy remains promising and awaits further confirmation in ongoing trials.

INTRODUCTION

Infant ALL is a rare disease, comprising <5% of childhood ALL.¹ Infants with ALL have a poor prognosis despite treatment intensification, whereas outcomes for older children have steadily improved to over 90%.² Particularly, infants with rearrangement of the lysine methyltransferase 2A (KMT2A-r) gene experience worse outcomes.³ These infants often relapse while on treatment, with up to 66% of relapses in the first year after diagnosis and 90% within 2 years.³

Blinatumomab is a bispecific T-cell engager molecule targeting CD19⁺ B cells and redirecting CD3⁺ T cells to trigger a cytotoxic response. Recently, the COG AALL1731 trial showed a survival benefit with the addition of blinatumomab to frontline therapy for children age 1-10 years with standard-risk B-ALL, which also included patients with KMT2A gene rearrangements.⁴ There is, however, limited evidence on blinatumomab's efficacy in infant KMT2A-r ALL. We conducted a pilot study to evaluate the safety and efficacy of adding blinatumomab to chemotherapy in infant KMT2A-r ALL. Initial findings showed promising short-term efficacy.⁵ Here, we present the long-term outcomes and secondary end points of this study, including toxicity and blinatumomab pharmacokinetics.

METHODS

We performed a prospective single-arm, interventional, multicenter, phase II study in infants (diagnosed at age <12 months) with KMT2A-r CD19⁺ B-ALL.⁵ Patients were treated with Interfant-06 induction³ before study inclusion and assigned to medium- or high-risk groups. We investigated the addition of a single cycle of blinatumomab (15 mcg/m2, daily, in a 28-day continuous infusion) after induction to standard Interfant-06 chemotherapy (Data Supplement, Fig S1, online only). Hematopoietic stem-cell transplantation (HSCT) was recommended in first complete remission post-MARMA for high-risk patients and for medium-risk patients with measurable residual disease of ≥5 × 10⁻⁴ before OCTADAD (Protocol, online only). The detailed methodology was previously described.⁵ Statistical analysis details are provided in the Data Supplement. This study was approved by independent ethics committees/institutional review boards of each center. Informed written consent was provided by parents/guardians.

Disease-free survival (DFS) was defined as the time from study entry to relapse, death from any cause, or second malignancy, whichever occurred first; overall survival (OS) as the time from study entry to death from any cause. Data were censored at the date of last contact when no event was observed. Long-term outcomes were compared with historical selected controls from the Interfant-06 study and with individually matched Interfant-06 controls, as previously reported.^5,6

Toxicity was summarized as rate and severity of infection. Administration of intravenous immunoglobulin (IVIg) and granulocyte-colony stimulating factor (G-CSF), both prescribed at investigator discretion, was also documented.

Pharmacokinetic steady-state concentrations (Css, pg/mL/d) of blinatumomab were obtained and used for calculating clearance (CL, L/h/m²) as CL = D/Css, where D is the daily infusion rate (µg/m²/h). Data on CL were compared with those of older children and adults.^7,8 The impact of potential covariates on CL was analyzed.

RESULTS

We enrolled 30 patients at 12 sites in Europe and Australia. The median age at diagnosis was 5 months (range, 0-11). The majority (70%) of patients were medium-risk, with the remainder (30%) being high-risk. All patients completed the full course of blinatumomab. Nine patients (all high-risk) had indication for HSCT, with one not receiving planned HSCT because of a blinatumomab-unrelated death. Two medium-risk patients proceeded to HSCT as per investigator's discretion. The median follow-up was 4.2 years (range, 3.2-6.0). Detailed patient characteristics are shown in the Data Supplement (Table S1).

The 4-year DFS was 83.3% (95% CI, 64.5 to 92.7), and the OS was 93.3% (95% CI, 75.9 to 98.3; Fig 1A). The 214 selected Interfant-06 controls not receiving blinatumomab had a 4-year DFS of 44.0% (95% CI, 37.0 to 50.8) and a 4-year OS of 60.2% (95% CI, 53.0 to 66.7; Figs 1B and 1C). The 4-year cumulative incidence of relapse was 13.3% (95% CI, 4.1 to 28.1) in this study population, compared with 49.6% (95% CI, 42.5 to 56.3) in the Interfant-06 controls (Fig 1D). When DFS comparison was based on individually matched controls, results were similar (Data Supplement, Fig S2). Notably, no further events were reported, compared with the previously published results which had a median follow-up of 2.2 years.⁵ Detailed events are described in the Data Supplement.

FIG 1.

Comparison of DFS, OS, and cumulative incidence of relapse of infants with KMT2A-rearranged ALL in this study with selected historical controls from Interfant-06. (A) DFS and OS in the current study; (B) DFS comparison between the current study and Interfant-06; (C) OS comparison between the current study and Interfant-06. (D) Cumulative incidence of relapse in the current study compared with Interfant-06. The comparison shown in (B)-(D) includes 214 patients from the Interfant-06 trial who were selected according to inclusion criteria used in the present study and for whom there were measurable residual disease data available at the end of induction. CIR, cumulative incidence of relapse; DFS, disease-free survival; OS, overall survival.

Severe infections (Common Terminology Criteria for Adverse Events grade ≥3) occurred in 70% (n = 21 of 30) at any point in the study, with 17% (n = 5 of 30) experiencing them during blinatumomab. No infection-related deaths occurred postinduction. Of a total of 95 infections, the most common were viral (36%), predominantly upper respiratory (31.6%). The lowest number was observed for blinatumomab (8 of 95 episodes, 8.4%), whereas the highest was observed for MARMA (27 of 95 episodes, 28.4%; Data Supplement, Table S2). Sites of infection per treatment phase are summarized in Figure 2. Nineteen patients (63%) received IVIg, and its use was most predominant during the blinatumomab cycle (40%). G-CSF was administered to a smaller proportion of patients (17%; Data Supplement, Table S3).

FIG 2.

Characterization of the type of infection by treatment phase (n = 95). Upper respiratory infection comprises upper respiratory infections, rhinitis infective, and pharyngitis; lower respiratory infections comprise bronchial infection; gastrointestinal infections comprise infectious enterocolitis and small intestine infection; skin infection comprises skin infection, lip infection, and papulopustular rash; device-related infection comprises device- and catheter-related infections; other infections/infestations were not otherwise characterized; Blin, Blinatumomab; IB, Protocol IB; MM, MARMA; MT, maintenance; OD, OCTADAD.

Mean blinatumomab Css levels were 706 ± 194 pg/mL/d, whereas the median CL value was 0.89 L/h/m² (range, 0.57-2.66). Median CL values did not differ between infants age below or above 6 months (data not shown). CL values were similar to those reported in older children (Table 1). None of the tested covariates had a significant impact on blinatumomab CL (Data Supplement, Table S4).

TABLE 1.

Cross-Generational Overview of the Pharmacokinetic Parameters of Blinatumomab

Age Group	Study	Mean Css (pg/mL/d)	Median CL (L/h/m2)
<12 months	Current study	706 ± 194 (n = 26)	0.89 [0.57-2.66] (n = 26)
<2 years	MT103-205 (r/r ALL)7	508 ± 215 (n = 8)	1.51 [1.00-2.17] (n = 8)
2-6 years		434 ± 353 (n = 15)	1.44 [0.33-10.7] (n = 21)
7-17 years		686 ± 510 (n = 11)	1.04 [0.60-5.84] (n = 16)
Adult cohorts	MT103-202 (MRD+ ALL)a	696 ± 147 (n = 19)	NA
	MT103-203 (MRD+ ALL)a	771 ± 312 (n = 32)	NA
	MT103-206 (r/r ALL)a	552 ± 237 (n = 34)	NA

NOTE. Adapted from Blincyto EPAR—Product Information, publicly available online.⁹

Abbreviations: Css, steady-state concentrations; CL, clearance; MRD, measurable residual disease; NA, data not available; r/r, relapsed/refractory.

^a Data from the MT103-202, MT103-203, and MT103-206 studies are derived from reference 8. Data are presented as mean ± standard deviation for normally distributed variables and as median [range] for non-normally distributed variables.

DISCUSSION

Our results show that adding blinatumomab to up-front standard therapy resulted in a sustained outcome benefit for infants with KMT2A-r ALL with a 4-year DFS and OS of 83% and 93%, respectively. This is noteworthy given that most existing evidence of blinatumomab's efficacy in children has been shown in a relapsed/refractory setting.¹⁰ The recent COG AALL1731 trial introduced two cycles of blinatumomab to up-front therapy in children with standard-risk B-ALL, showing improved 3-year DFS in comparison with chemotherapy alone (96% v 88%).⁴ Building on our previous findings, we now demonstrate extended blinatumomab efficacy, with no further events observed.⁵ This highlights the benefit of blinatumomab beyond the historically defined high-risk recurrence period, comprising the 2-year treatment window.³

Most patients in our cohort experienced at least one infection during treatment, with two thirds experiencing a severe infection. This is unsurprising since the combination of blinatumomab-derived B-cell aplasia and intensive chemotherapy after blinatumomab increases susceptibility to prolonged immunosuppression and potential infection.³ Given the vulnerability of infants with ALL to infectious toxicity, it is remarkable that no infection-related deaths occurred, as opposed to the 4% infectious mortality rate postinduction on Interfant-06.³ In addition, infection rates were 2-3 times higher in later phases of treatment than during blinatumomab, following a similar pattern noted in the COG AALL1731 study.⁴

With regard to pharmacokinetics, blinatumomab CL did not differ from previously reported values in older children and was not affected by potential covariates. This is corroborated by previous findings¹¹ and supports not adjusting blinatumomab dosing for infants.

The limitations to our study include study design, which did not allow for a randomized controlled trial of blinatumomab. The poor outcomes of the previous Interfant-06 study were prohibitive of a control arm, and hence, we compared results with a clinically matched Interfant-06 cohort. In addition, a direct comparison of infectious events with the historical protocol was not possible because of the use of different adverse event classification systems.

In conclusion, we demonstrate the striking and durable benefit of blinatumomab in long-term survival outcomes for infants with KMT2A-r ALL. While the FDA has now approved blinatumomab from age 1 month,¹² future work should clarify the implications of replacing more intensive blocks of chemotherapy with additional blinatumomab cycles. Results from contemporary studies like Interfant-21 (ClinicalTrials.gov identifier: NCT05327894)¹³ and COG AALL2321 (ClinicalTrials.gov identifier: NCT06317662)¹⁴ are awaited to further confirm the impact of blinatumomab in infants with KMT2A-r ALL.

DATA SHARING STATEMENT

A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-25-01806.

AUTHOR CONTRIBUTIONS

Conception and design: Miguel Vieira Martins, Paola de Lorenzo, Rishi S. Kotecha, Andishe Attarbaschi, Gabriele Escherich, Karsten Nysom, Jan Stary, Alina Ferster, Benoit Brethon, Franco Locatelli, Martin Schrappe, Maria G. Valsecchi, Alwin D.R. Huitema, Rob Pieters, Inge M. van der Sluis

Administrative support: Peggy E. Scholte-van Houtem

Provision of study materials or patients: All authors

Collection and assembly of data: Miguel Vieira Martins, Paola de Lorenzo, Peggy E. Scholte-van Houtem, Maria G. Valsecchi, Rob Pieters, Inge M. van der Sluis

Data analysis and interpretation: All authors

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Sustained Benefit of Blinatumomab in Infants With KMT2A-Rearranged ALL: Long-Term Outcomes, Toxicity, and Pharmacokinetics

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