Extramedullary disease relapse and progression after blinatumomab therapy for treatment of acute lymphoblastic leukemia

Abstract

BACKGROUND: Blinatumomab has demonstrated encouraging activity in relapsed/refractory (r/r) and minimal residual disease-positive (MRD+) acute lymphoblastic leukemia (ALL). Extramedullary disease (EMD) relapse or relapse with CD19-disease has been observed after blinatumomab therapy in patients with r/r or MRD+ ALL. However, the pathophysiology and risk factors of treatment failure are not fully understood. METHODS: This study retrospectively reviewed the outcomes of adult patients with B-cell ALL treated with blinatumomab (n = 132) for either r/r (n = 103) or MRD+ disease (n = 29) at the authors' center (2013-2021) and analyzed factors associated with treatment response and EMD failure. RESULTS: The overall response rate was 64%. A lower marrow blast burden before blinatumomab (P = .049) and no history of previous EMD (P = .019) were significantly associated with a higher response. Among the patients who responded to blinatumomab, 56% underwent consolidation with allogeneic transplantation. Blinatumomab failure was observed in 89 patients; 43% of these patients (n = 38) either progressed or relapsed at extramedullary sites. A history of extramedullary involvement (53% vs 24%; P = .005) and retention of CD19 expression at the time of relapse/progression (97% vs 74%; P = .012) were associated with a higher risk for extramedullary failure. Central nervous system (CNS) failure after blinatumomab was encountered in 39% of the patients with EMD. CONCLUSIONS: A history of EMD predicted an inferior response to blinatumomab therapy with a higher risk for relapse/ progression at extramedullary sites (particularly CNS). Consolidation with allogenic transplantation in patients who primarily responded to blinatumomab did not abrogate the risk of extramedullary relapse. The incorporation of extramedullary assessment and the intensification of CNS prophylaxis may help in addressing extramedullary failure.

Sequencing antigen‐targeting antibodies and cellular therapies in adults with relapsed/refractory B‐cell acute lymphoblastic leukemia

“…Retaining CD19 expression after failure of blinatumomab therapy is a prerequisite to proceed with CD19 CAR T‐cell therapy. Although some patients treated with blinatumomab will lose the expression of CD19 antigen posttherapy, 12,33,37,38,93 we have observed the re‐expression of CD19 antigen in a fraction of these patients after treatment with inotuzumab or other targeted therapies 97 . Outcomes of CD19‐targeting therapies in CD19 re‐expressors after prior progression with a CD19– or CD19 low expressor subclone remain poorly characterized.…”

“…Studies evaluating blinatumomab in r/r ALL have consistently demonstrated a correlation between pretreatment leukemia burden and response to therapy 3,13,33 . Responses are superior in patients with lower disease burden, especially in the MRD+ setting (MRD response = 80%) 11 and r/r ALL with pretreatment marrow blasts <50% (CR/CRi of 66%–73%) 3,13 .…”

“…EMD is a common manifestation of relapsed ALL, especially after failure of alloHCT 36 . EMD involvement is often observed at the time of blinatumomab failure 10,33,37,38 . In a retrospective analysis of adults with r/r ALL treated with blinatumomab, 36% of blinatumomab‐refractory patients and 50% of blinatumomab responders who subsequently relapsed presented with evidence of EMD with or without marrow involvement, including 21% and 33% who manifested as isolated EMD at the time of progression or relapse, respectively 33 .…”

An Unusual Presentation of Extramedullary Relapse Following Blinatumomab in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

“…Several studies have previously reported and described EMR after treatment with blinatumomab. Notably, Aldoss et al [ 9 , 11 ] in two retrospective studies including patients treated with blinatumomab for R/R ALL reported EMR rates ranging from 32% to 49% among initial responders to blinatumomab. Sites of EMR included the CNS, kidney, lymph node, muscle, chest wall, and nasopharynx.…”

Efficacy and safety of CD19 CAR-T cell therapy for acute lymphoblastic leukemia patients relapsed after allogeneic hematopoietic stem cell transplantation

“…Still, patients treated with these antibodies do not have long-term response and maintenance of longer RFS remains a major issue [4,5]. In addition, whether blinatumomab can penetrate the blood-brain barrier (BBB) remains unclear, and there is currently no obvious evidence that B-ALL patients with CNS involvement respond well [119]. In contrast, many studies have provided evidence that CAR-T cells can penetrate the BBB [31,120].…”