CD19‐negative relapse in adult patients with relapsed/refractory B‐cell precursor acute lymphoblastic leukemia following treatment with blinatumomab‐a post hoc analysis

To the Editor: CD19 is expressed on B-cells and is a therapeutic target for patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blinatumomab is a CD3/CD19-directed BiTE (bispecific T-cell engager) molecule that redirects CD3-positive T-cells to engage and lyse CD19-expressing B-cells. The randomized, multicenter, phase 3 TOWER study (NCT02013167) enrolled 405 patients with Philadelphia chromosome (Ph)–negative relapsed/refractory (R/R) BCP-ALL (blinatumomab n = 271, chemotherapy n = 134). Patients treated with blinatumomab demonstrated a significantly longer overall survival (OS; median OS, blinatumomab vs. chemotherapy, 7.7 months vs. 4.0 months; hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55–0.93; p = 0.01) and a higher rate of event-free survival (EFS; 6-month estimates, blinatumomab vs. chemotherapy, 31.0%, vs. 12.0%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery [CR/CRh/CRi], or death, 0.55; 95% CI, 0.43 to 0.71; p < 0.001) compared with those treated with chemotherapy. The phase 2, open-label, single-arm, multicenter ALCANTARA study (NCT02000427) evaluated the efficacy and safety of blinatumomab in adults with Ph–positive R/R BCP-ALL. In this study, 45 patients with disease progression after treatment with ≥1 second or later-generation tyrosine kinase inhibitor (TKI) or intolerant to second or later-generation TKI, and intolerant or refractory to imatinib received two cycles of blinatumomab. The median relapse-free survival was 6.7 months, and the median OS was 7.1 months. Although most patients respond to blinatumomab, a subset of patients with R/R BCP-ALL relapse with loss of expression of CD19 on leukemic blasts. The objective of this retrospective post hoc analysis was to summarize the rate of CD19-negative relapse in adult patients with R/R BCP-ALL following treatment with blinatumomab from the two pivotal trials, TOWER and ALCANTARA, respectively. Detailed descriptions of the study design and patient eligibility for the TOWER and ALCANTARA studies and definition for CR/CRh/CRi have been previously reported. All patients enrolled in the TOWER and ALCANTARA studies expressed CD19 at baseline. Patients with disease relapse following treatment with blinatumomab from the TOWER and ALCANTARA studies were identified based on the assessment by the local investigators. Of these patients, those with >5% leukemic blasts in the bone marrow were considered for this analysis. These patients were assessed for CD19 expression using immunocytochemistry analysis (Data S1) based on which they were categorized as CD19-negative or CD19-positive. CD19-negativity was defined as the absence of any detectable CD19 on BCP-ALL blasts. The rate of CD19-negative or CD19-positive relapse was calculated as a percentage of the number of patients who achieved CR/CRh/CRi. Patients with refractory disease were defined as those with progressive disease, non-response to blinatumomab, or partial response upon treatment with blinatumomab and were categorized as CD19-negative or CD19-positive. Time to hematologic relapse was defined as the time from CR/CRh/CRi until the detection of relapse (>5% blasts in the bone marrow). EFS was defined as the time from randomization until relapse following CR/CRh/CRi, or death. OS was defined as the time from randomization to death from any cause. An analysis of the cumulative incidence of CD19-negative relapse in patients who achieved CR/CRh/CRi in response to treatment with blinatumomab from the TOWER and ALCANTARA studies with respect to the time to hematologic relapse was performed. Competing events for this analysis were CD19-positive relapse, extramedullary relapse, progressive disease, and death prior to relapse. All patients signed a consent form in accordance with the Declaration of Helsinki; the study was approved by the Institutional Review Boards of the investigation sites. Baseline characteristics of patients from the TOWER and ALCANTARA studies included in this analysis are shown in Supplementary Table 1 and Supplementary Table 2, respectively. In the TOWER study, a total of 271 patients with R/R BCP-ALL received ≥1 cycle of blinatumomab, of which 119 patients achieved CR/CRh/ CRi within 12 weeks from initiation of treatment (Table 1). Upon a median follow-up of 8.3 months, the percentage of patients with CD19-negative relapse was 8.4% (10/119). Of the 75 patients who were refractory to treatment with blinatumomab, 6 patients (8.0%) were CD19-negative (Table 1 and Supplementary Table 3). Overall, of Received: 23 January 2023 Revised: 28 April 2023 Accepted: 18 May 2023

plete remission with full, partial, or incomplete hematologic recovery [CR/CRh/CRi], or death, 0.55; 95% CI, 0.43 to 0.71; p < 0.001) compared with those treated with chemotherapy. The phase 2, open-label, single-arm, multicenter ALCANTARA study (NCT02000427) evaluated the efficacy and safety of blinatumomab in adults with Ph-positive R/R BCP-ALL. 2 In this study, 45 patients with disease progression after treatment with ≥1 second or later-generation tyrosine kinase inhibitor (TKI) or intolerant to second or later-generation TKI, and intolerant or refractory to imatinib received two cycles of blinatumomab. The median relapse-free survival was 6.7 months, and the median OS was 7.1 months.
Although most patients respond to blinatumomab, a subset of patients with R/R BCP-ALL relapse with loss of expression of CD19 on leukemic blasts. The objective of this retrospective post hoc analysis was to summarize the rate of CD19-negative relapse in adult patients with R/R BCP-ALL following treatment with blinatumomab from the two pivotal trials, TOWER and ALCANTARA, respectively.
Detailed descriptions of the study design and patient eligibility for the TOWER and ALCANTARA studies and definition for CR/CRh/CRi have been previously reported. 1,2 All patients enrolled in the TOWER and ALCANTARA studies expressed CD19 at baseline. Patients with disease relapse following treatment with blinatumomab from the TOWER and ALCANTARA studies were identified based on the assessment by the local investigators. Of these patients, those with >5% leukemic blasts in the bone marrow were considered for this analysis. These patients were assessed for CD19 expression using immunocytochemistry analysis (Data S1) based on which they were categorized as CD19-negative or CD19-positive. CD19-negativity was defined as the absence of any detectable CD19 on BCP-ALL blasts.
The rate of CD19-negative or CD19-positive relapse was calculated as a percentage of the number of patients who achieved CR/CRh/CRi. Patients with refractory disease were defined as those with progressive disease, non-response to blinatumomab, or partial response upon treatment with blinatumomab and were categorized as CD19-negative or CD19-positive. Time to hematologic relapse was defined as the time from CR/CRh/CRi until the detection of relapse (>5% blasts in the bone marrow). EFS was defined as the time from randomization until relapse following CR/CRh/CRi, or death. OS was defined as the time from randomization to death from any cause. An analysis of the cumulative incidence of CD19-negative relapse in patients who achieved CR/CRh/CRi in response to treatment with blinatumomab from the TOWER and ALCANTARA studies with respect to the time to hematologic relapse was performed. Competing events for this analysis were CD19-positive relapse, extramedullary relapse, progressive disease, and death prior to relapse. All patients signed a consent form in accordance with the Declaration of Helsinki; the study was approved by the Institutional Review Boards of the investigation sites. were CD19-negative (Table 1 and Supplementary Table 3). Overall, of the 194 patients who achieved CR/CRh/CRi or had refractory disease, 8.2% of patients were CD19-negative (Table 1). In the ALCANTARA study, 45 patients were enrolled and treated with blinatumomab of which 16 patients achieved CR/CRh (Table 1). Two (12.5%) of these 16 patients experienced a CD19-negative relapse. Of the 18 patients who were refractory to blinatumomab, none of the patients were CD19-negative (Table 1 and Supplementary Table 3). Overall, of the 34 patients who achieved CR/CRh/CRi or had refractory disease, the percentage of patients who were CD19-negative was 5.9% (Table 1).
Of the 135 patients who achieved CR/CRh/CRi in response to treatment with blinatumomab from the TOWER and ALCANTARA studies (119 from TOWER and 16 from ALCANTARA), the cumulative incidence of CD19-negative relapse was estimated in 133 patients; 2 patients for whom the status of expression of CD19 was unclear were not included in the analysis (Supplementary Figure 1A). The estimated cumulative incidence of CD19-negative relapse at 3 months and 10 months from CR/CRh/CRi was about 2.0% and 11.0%, respectively. The cumulative incidence of CD19-negative relapse in patients from TOWER and ALCANTARA is shown in Supplementary Figure 1B and Supplementary Figure 1C, respectively. Assessment of CD22, CD79a, and CD10 in patients with CD19-negative relapse from both the TOWER and ALCANTARA studies showed that most patients expressed CD22 (Supplementary Table 4). The status of expression of CD22, CD79a, CD13, and CD10 in patients who were refractory to blinatumomab and were CD19-negative is shown in Supplementary  Table 7).
T A B L E 1 Patients with CD19-negative and CD19-positive relapse following treatment with blinatumomab from the TOWER and ALCANTARA studies. Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CD, cluster of differentiation; CR, complete remission with full hematologic recovery; CRh, complete remission with partial hematologic recovery; CRi, complete remission with incomplete hematologic recover. a Remission rate was measured in patients with CR/CRh/CRi, at the end of 12 weeks of blinatumomab for TOWER, and in patients with CR/CRh at the end of 8 weeks of blinatumomab for ALCANTARA. Complete remission was defined as 5% or less bone marrow blasts and no evidence of disease and was further characterized according to the extent of recovery of peripheral blood counts as follows: complete remission with full recovery (CR) was defined as patients with platelet count of >100 000/μL and absolute neutrophil count of >1000/μL; complete remission with partial recovery (CRh) was defined as patients with platelet count of >50 000/μL and absolute neutrophil count of >500/μL; complete remission with incomplete recovery (CRi) was defined as patients with platelet count of >100 000/μL or absolute neutrophil count of >1000/μL. b Relapsed patients had >5% bone marrow blasts and were categorized as such per assessment by the local investigators.
c Refractory patients were defined as those with progressive disease, non-response, or partial response upon treatment with blinatumomab and were categorized as such per assessment by the local investigators.