Predictors of Blinatumomab Therapy Failure and CD19-Negative Relapse in Adult B-Cell ALL

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Acute lymphoblastic leukemia (ALL) is a hematologic malignancy in which the prognosis for adults with newly diagnosed disease has improved over the last decades with the use of intensified protocols.^1,2 In addition, the landscape of ALL has changed with the introduction of targeted therapies such as tyrosine kinase inhibitors, bispecific T-cell engager therapy, and antibody-drug conjugates. Blinatumomab (Blincyto; Amgen Inc) is a bispecific CD19-CD3 T-cell engager and was the first FDA-approved bispecific on the market. It is currently FDA approved for relapsed/refractory (R/R) ALL, minimal residual disease–positive (MRD+) ALL, and for MRD-negative (MRD–) consolidation.

Although blinatumomab is being used more frequently earlier on in therapy, therapy failure is common and can present as relapse with features of antigen loss and extramedullary disease (EMD).³ Furthermore, these mechanisms and factors associated with EMD and CD19-negative (CD19–) disease have yet to be described.

At the City of Hope, we performed a retrospective analysis of 267 adult patients with B-cell ALL who received at least 1 cycle of treatment between 2012 and 2024, the results of which we presented at the 66th American Society of Hematology Annual Meeting and Exposition in San Diego, California.⁴ As a part of our retrospective analysis, we examined and analyzed ALL genetic features using next-generation sequencing, cytogenetics, and/or microarray. We also analyzed response to blinatumomab and described patterns of failure according to patients and other clinical factors.

Patient Clinical and Demographic Features

Blinatumomab was administered for R/R disease (n = 150), MRD+ disease (n = 88), and consolidation in patients with MRD–disease (n = 19), and up front as induction therapy (n = 10). The median age of patients was 40 years (range, 18-88 years), and the majority of patients were of Hispanic background (n = 186, 70%). The median number of prior lines of therapies was 1 (range, 0-5) and there were 26 (10%) patients with prior allogeneic hematopoietic cell transplantation (allo-HCT) before blinatumomab. Among the patients who underwent comprehensive genetic testing, 80 (44%) had detectable myeloid mutations (frequency in order: TP53, KRAS, NRAS, FLT3, DNMT3A, TET2, ASXL1, RUNX1, IDH1, IDH2, PHF6, and PTPN11) and 61 (33%) had IKZF1 alterations. Among all treated patients in our group, 50 (19%) had Philadelphia chromosome–positive (Ph+) disease, 80 (30%) had Ph-like disease, 39 (15%) had normal karyotype (NK), 30 (11%) had TP53 mutations (TP53m), 14 (5%) had complex karyotype without TP53m, 7 (3%) had KMT2A rearrangements (KMT2Ar), and 9 (3%) had PAX5 alterations (PAX5a).

Patient Response Rates and Univariate/Multivariate Analysis

For patients treated for R/R B-ALL, the overall complete remission (CR)/CR with incomplete hematological recovery (CRi) rate was 59% (n = 89). Respective CR/CRi rates among these genetic subgroups were 54% for Ph+ disease, 66% for Ph-like disease, 74% for NK, and 59% for TP53m (P = not significant). CR/CRi rates for patients with and without myeloid mutations were 60% and 73% (P = .29), respectively, and for patients with and without IKZF1 alteration, the rates were 61% and 68% (P = .74), respectively. There were 99 patients who underwent allo-HCT consolidation after blinatumomab in CR/CRi. Only those with pretreatment high disease burden (≥ 50% bone marrow [BM] blasts; P < .01) and active EMD (P < .01) were associated with an inferior CR/CRi rate.

Among 169 patients in CR/CRi post blinatumomab, 90 (53%) remained alive and in remission and 79 (47%) relapsed, including 3 with unknown CD19 expression status, 22 (13%) with CD19– relapse, and 54 (32%) with CD19+ relapse. The median times to CD19– and CD19+ relapse were 6 and 7.4 months, respectively. The presence of myeloid mutations (P < .01), TP53m (P < .01), blinatumomab administered in R/R setting (P < .01), the use of blinatumomab as an earlier line of therapy (0-1 lines) (P < .01), preinfusion high disease burden (P = .03), and not receiving allo-HCT after response to blinatumomab (P < .01) were associated with higher risk for CD19– relapse in univariate analysis. CD19– relapse represented 77% (n = 13) and 75% (n = 3) of relapsed cases with TP53m and KMT2Ar, respectively; CD19– disease did not occur for relapsed patients with Ph+ disease (n = 10), complex cytogenetics without TP53m (n = 7), Ph-like disease with non-CRLF2r (n = 3), or PAX5a (n = 2). CD19–relapse was observed among 56% and 10% of relapsed patients with and without myeloid mutations, respectively, and in 11% and 42% of patients with and without IKZF1 alterations, respectively.

In multivariate analysis, TP53m was associated with an increased risk of CD19– relapse (HR, 5.03; 95% CI, 1.4-18.1; P < .01) and post blinatumomab allo-HCT consolidation was associated with lower risk of CD19–relapse (HR, 0.11; 95% CI, 0.03-0.44; P < .01).

Patient Relapse Description

Among patients in CR/CRi post blinatumomab, 22% had EMD with or without BM relapse, 25% had only BM relapse, and 53% remained alive and did not relapse. The median times for EMD relapse and BM-only relapse were 5.9 and 8.7 months, respectively. In multivariate analysis, allo-HCT consolidation was associated with lower risk for EMD relapse (HR, 0.17; 95% CI, 0.08-0.37; P < .01).

Conclusions

With the recent FDA approval for using blinatumomab in MRD– consolidation and ongoing studies evaluating the use of frontline blinatumomab, further investigations are needed to evaluate the interplay between leukemia biology and blinatumomab therapy failure. In our analysis, certain leukemia features may predict blinatumomab failure after response despite lack of impact on initial response. The presence of TP53m was associated with a significantly higher risk for CD19– relapse as an immune escape mechanism following blinatumomab and warrants further analysis.

REFERENCES

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3. Aldoss I, Otoukesh S, Zhang J, et al. Extramedullary disease relapse and progression after blinatumomab therapy for treatment of acute lymphoblastic leukemia. Cancer. 2022;128(3):529-535. doi:10.1002/cncr.33967

4. Aldoss I, Li J, Zhang J, et al. TP53 mutations increased the risk of CD19 negative relapse following blinatumomab in adults with B-cell acute lymphoblastic leukemia (B-ALL). Blood. 2024;144(suppl 1):729. doi:10.1182/blood-2024-208674