Association of leukemic molecular profile with efficacy of inotuzumab ozogamicin in adults with relapsed/refractory ALL

Abstract

The phase 3 INO-VATE trial demonstrated higher rates of remission, measurable residual disease negativity, and improved overall survival for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (InO) vs standard-of-care chemotherapy (SC). Here, we examined associations between genomic alterations and the efficacy of InO. Of 326 randomized patients, 91 (InO, n = 43; SC, n = 48) had samples evaluable for genomic analysis. The spectrum of gene fusions and other genomic alterations observed was comparable with prior studies of adult ALL. Responses to InO were observed in all leukemic subtypes, genomic alterations, and risk groups. Significantly higher rates of complete remission (CR)/CR with incomplete count recovery were observed with InO vs SC in patients with BCR::ABL1-like ALL (85.7% [6/7] vs 0% [0/5]; P = .0076), with TP53 alterations (100% [5/5] vs 12.5% [1/8]; P = .0047), and in the high-risk BCR::ABL1- (BCR::ABL1-like, low-hypodiploid, KMT2A-rearranged) group (83.3% [10/12] vs 10.5% [2/19]; P < .0001). This retrospective, exploratory analysis of the INO-VATE trial demonstrated potential for benefit with InO for patients with R/R ALL across leukemic subtypes, including BCR::ABL1-like ALL, and for those bearing diverse genomic alterations. Further confirmation of the efficacy of InO in patients with R/R ALL exhibiting the BCR::ABL1-like subtype or harboring TP53 alterations is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT01564784.

Graphical abstract

Figure 1.

Gene fusions of interest by ALL subtype. The most common subtypes across treatment arms were BCR::ABL1⁺, BCR::ABL1–like, low hypodiploidy, KMT2A rearranged, and DUX4 rearranged. The most common non–BCR::ABL1 rearrangements were IGH::CRLF2 detected in the BCR::ABL1–like subtype, and KMT2A::AFF1 detected in the KMT2A rearranged subtype. Oncoprint displays cases of both canonical and noncanonical fusion orientation. The numbers in parentheses denote the number of patients carrying that gene fusion.

Figure 2.

Common nonfusion genomic alterations by ALL subtype and molecular pathway. Among nonrearrangement genomic alterations, sequence mutations of chromatin-modifying genes were common. Other common gene alterations included TP53, NOTCH1, and KRAS. The numbers in brackets denote the number of patients carrying that genomic alteration.

Figure 3.

Efficacy outcomes with InO or SC by ALL subtype. (A) CR/CRi rates were higher with InO than with SC across leukemic subtypes, with the difference reaching statistical significance in the BCR::ABL1–like subtype. (B) A trend toward benefit with InO was observed across leukemic subtypes for PFS; and (C) across most subtypes for OS. ^aCIs were approximated using nominal distribution when ≥5 patients were in both the CR/CRi and non–CR/CRi subgroups. Where <5 patients were in either subgroup, exact method was used; ^bincluded DUX4, CDX2/UBTF, MEF2D, TCF3::PBX1, and ZNF384; ^cincluded hyperdiploid; ^dincluded B-other, PAX5alt, and ZEB2/CEBP.

Figure 4.

Efficacy outcomes with InO or SC by select genomic alterations. (A) Across genomic alterations, there was a potential for response to InO treatment, and CR/CRi rates were significantly higher in patients with TP53 alterations who received InO. (B) A trend toward a PFS benefit was observed across genomic alterations; however, (C) no such trend was observed for OS. ^aAll patients bearing an alteration in a gene with an overall alteration prevalence n of at least 8; ^bCIs were approximated using nominal distribution when ≥5 patients were in both the CR/CRi and non–CR/CRi subgroups. Where <5 patients were in either subgroup, exact method was used.

Figure 5.

Efficacy outcomes with InO or SC by leukemic subtype–based risk group. (A) Response to InO was observed across risk groups group based on a classification of leukemic subtypes. In the high-risk BCR::ABL1⁻ group, CR/CRi rates were significantly higher with InO compared with SC. (B) A trend toward a benefit with InO was evident across most risk groups for PFS; (C) OS. ^aCIs were approximated using nominal distribution when ≥5 patients were in both the CR/CRi and non–CR/CRi subgroups. Where <5 patients were in either subgroup, exact method was used. int, intermediate.