Introduction:

Adults and AYA patients (pts) with relapsed/refractory (R/R) B-ALL have a poor prognosis, despite new therapies approved since 2015. After each relapse, R/R B-ALL becomes more difficult to treat due to its aggressiveness, acquired resistance, and intolerance to intensive therapy. With increasing use of the bispecific T-cell engager antibody blinatumomab (blin) earlier in treatment and few new therapies for later R/R B-ALL lines, pts may receive retreatment with blin or other therapies used in prior lines. This study describes pts receiving blin rechallenge.

Methods:

This retrospective, observational cohort study used pt data from the US nationwide longitudinal Flatiron Health Research Database from January 1, 2014 to March 31, 2024. Pts aged ≥12 years with an initial B-ALL diagnosis who had received ≥1 prior line of therapy (LoT) with blin and received blin in a later treatment line (rechallenge) were included. Real-world complete response rate (rwCRR; defined as <5% bone marrow blasts, morphologic response [clinician assessed], and the absence of extramedullary disease), real-world duration of response (rwDoR; defined as time from 1st confirmed complete response assessment to progression/relapse or death), adverse events (AEs) and number of blin cycles were evaluated at 1st blin exposure and rechallenge.

Results:

Of 617 pts with ≥1 LoT with blin, 36 (6%) pts had 40 rechallenges. 281 pts received 1st-line blin (1L), 268 pts received 2nd-line blin (2L; 5 [2%] were receiving rechallenge), and 71 pts received 3rd-line blin (3L; 18 [25%] were receiving 1st rechallenge). Of the 40 blin rechallenges, 5 were in 2L, 19 in 3L, and 16 in fourth-line or later (4L+). In the 3L rechallenge group, 1st blin use was in 1L (3 pts [16%]) or 2L (16 pts [84%]). In the 4L+ group, 1st blin use was in 1L (2 pts [13%]), 2L (9 pts [56%]) or 3L (5 pts [31%]).

In the 36 rechallenge pts; 5 received their 1st rechallenge in 2L, 18 in 3L, and 13 in 4L+. At 1st rechallenge, median age was 51 yrs, 64% of pts were male, 28% were Philadelphia chromosome (Ph)-positive, 56% Ph-negative, and 39% had undergone hematopoietic stem cell transplantation (HSCT). Across LoTs, rwCRR was 56% after 1st blin exposure and 39% after 1st rechallenge. rwCRR was 40% with 2L rechallenge (n=5), 33% with 3L rechallenge (n=18), and 46% with 4L+ rechallenge (n=13). The median rwDoR was 66.6 months (mo) after 1st exposure (n=15) and 7.9 mo after rechallenge (n=10). Median rwDoR was 5.2 mo with 2L blin rechallenge (n=1), 17.2 mo with 3L blin rechallenge (n=4), and 8.0 mo with 4L+ blin rechallenge (n=5).

At both 1st exposure and 1st blin rechallenge in any LoT, the rate of AEs was 25%. The incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) was lower in 1st exposure vs rechallenge (8% vs 17%), but cytokine release syndrome (CRS) incidence was similar (14% vs 11%). In the rechallenge, ICANS incidence was 20% in 2L, 11% in 3L, and 23% in 4L+. CRS incidence was higher in later rechallenge lines vs 2L (2L, 0%; 3L, 17%; 4L+, 8%). The median number of blin cycles in the rechallenge was 3 (IQR: 2, 4). Of the 36 pts receiving blin rechallenge, 5 (14%) went on to undergo HSCT and 1 (3%) received chimeric antigen receptor T-cell (CAR-T) therapy.

Conclusions:

This was the largest real-world analysis of blin rechallenge in pts with R/R B-ALL. Of pts who had ≥1 line of blin, 6% received rechallenge. Pts received blin rechallenge at any point after initial blin exposure, although more commonly directly after 1st exposure. Pts responded to blin rechallenge but rwCRR and median rwDOR were inferior to initial exposure. The incidence of ICANS in rechallenge pts were higher than previously reported and incidence of CRS were higher in later rechallenge lines vs 2L, suggesting that ICANS and CRS risk is high despite prior blin exposure. This may be because pts had a higher blast count before rechallenge. Most pts did not receive the indicated number of cycles of blin, possibly due to interruption of cycles during rechallenge or early discontinuation due to poor response or toxicity. Few pts receiving blin rechallenge underwent HSCT or received CAR-T, likely due to lack of response or low commercial availability, respectively. Blin rechallenge is feasible in pts with R/R B-ALL, but rwCRR and rwDOR are limited. New treatment strategies are needed to provide effective and well-tolerated options after blin rechallenge and for blin-refractory pts.

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2025
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