Correlates of resistance and relapse during blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia

Abstract

We retrospectively analyzed 65 patients with refractory/relapsed (r/r) ALL who were treated with blinatumomab for predictors of leukemia response as well as clinical patterns of relapse and resistance with particular focus on downregulation of CD19 expression and extramedullary disease (EM-ALL). The complete remission (CR) rate was 51%, and 15 (45%) responders underwent allogeneic hematopoietic cell transplantation (HCT) in CR. High leukemia burden (bone marrow blasts >50%) (P = .02), history of prior EM-ALL (P = .005), and active EM-ALL at the time of initiating blinatumomab (P = .05) predicted lower CR rate. Among refractory cases, 13 (41%) had evidence of EM-ALL progression, and CD19 expression was negative or dim in 18% and 23%, respectively. Among responders, 20 (61%) subsequently relapsed among whom EM-ALL relapse occurred in 8 (40%) patients, and CD19 expression was negative or dim in 35 and 6% of evaluable cases, respectively. Pretreatment moderate/strong CD19 expression (P = .01) and history of prior EM-ALL during ALL course (P = .04) were risk factors for developing EM-ALL at progression/relapse. However, no pretreatment factors predicted progression/relapse with CD19-negative ALL. Overall-survival (OS) and even-free survival were improved for patients underwent allogeneic HCT compared to responders who did not. Furthermore, OS was superior for patients responded to blinatumomab compared to those who did not. Extramedullary and CD19-negative disease are common during blinatumomab failure in r/r ALL. In addition to high leukemia burden, concurrent or prior history EM-ALL were associated with lower response to blinatumomab. Higher CD19 expression as well as prior history of EM-ALL were associated with EM-ALL at the time of blinatumomab failure.

Cytokine Release Syndrome With the Novel Treatments of Acute Lymphoblastic Leukemia: Pathophysiology, Prevention, and Treatment

“…It is worth noting that short-term use of steroids on the other hand has not been shown to negatively impact the CD19CAR efficacy in the ZUMA-1 trial. Steroids are also effective in controlling CRS symptoms during blinatumomab therapy, and steroids have shown no to little impact on blinatumomab activity [5,31]. We have demonstrated that prolonged administration of steroids (≥ 1 week) was common during the first cycle of blinatumomab therapy for r/r ALL, but use was not different between responders and nonresponders (39% vs. 41%, p = 0.92) and did not impact survival afterward [31].…”

“…The recommendation for pre-treatment with dexamethasone is also applied before dose escalation and in the event of therapy interruption. Importantly, the concern that dexamethasone leads to impairing effector T cells and reduced blinatumomab efficacy has not been demonstrated [5,31].…”

CD19-targeted immunotherapies for treatment of patients with non-Hodgkin B-cell lymphomas

“…Antigen loss has also been reported in other lymphoma and leukemia patient populations following CAR-T cell therapy [81][82][83][84]. Examination of biopsies before CD19 CAR-T therapy and after relapse in B-ALL patients has revealed hemizygous deletions spanning the CD19 locus as well as frameshift mutations in some patients [85].…”

“…CD19 loss is a less common (3-8% in B-ALL patients) in patients relapsing after blinatumomab , possibly through disruption of CD19 membrane trafficking [86]. Interestingly, extramedullary relapses in B-ALL are more frequent following blinatumomab treatment, but have not be reported in CART-T cell trials [83].…”

T lymphocytes as therapeutic arsenal for patients with hematological malignancies

“…Both events can be treated with drug interruption, high-dose steroids and some patients may require tocilizumab [78 & ]. Treatment resistance and relapse after blinatumomab correlates with leukemia burden, extramedullary ALL, PD-L1 blast expression [82] and circulating regulatory T cells [83]. The immunological pressure drives CD19À relapses in 10-20% of patients, due to CD19 expression loss or disrupted membrane trafficking [84], selection of preexisting CD19À clones [85] or lineage switch [86], indicating the need to carefully monitor escape variants.…”