Project EVOLVE: an international analysis of postimmunotherapy lineage switch, an emergent form of relapse in leukemia

Abstract

Lineage switch (LS), defined as the immunophenotypic transformation of acute leukemia, has emerged as a mechanism of relapse after antigen-targeted immunotherapy, which is associated with dismal outcomes. Through an international collaborative effort, we identified cases of LS after a host of antigen-targeted therapies (eg, CD19, CD22, CD38, and CD7), described how LS was diagnosed, reviewed treatment approaches, and analyzed overall outcomes for this form of postimmunotherapy relapse. Collectively, 75 cases of LS were evaluated, including 53 (70.7%) cases of B-cell acute lymphoblastic leukemia (B-ALL) transforming to acute myeloid leukemia (AML), 17 (22.7%) cases of B-ALL transforming to mixed phenotypic acute leukemia (MPAL)/acute leukemias of ambiguous lineage (ALAL), and 5 (6.7%) cases of rare LS presentation (ie, T-cell ALL to AML). An additional 10 cases with incomplete changes in immunophenotype, referred to as "lineage drift" were also described. With a primary focus on the 70 cases of LS from B-ALL to AML or MPAL/ALAL, LS emerged at a median of 1.5 months (range, 0-36.5) after immunotherapy, with 81.4% presenting with LS within the first 6 months from the most proximal immunotherapy. Although most involved KMT2A rearrangements (n = 45, 64.3%), other rare cytogenetic and/or molecular alterations were uniquely observed. Treatment outcomes were generally poor, with remission rates of <40%. The median overall survival after LS diagnosis was 4.8 months. Outcomes were similarly poor for those with rare immunophenotypes of LS or lineage drift. This global initiative robustly categorizes lineage changes after immunotherapy and, through enhanced understanding, establishes a foundation for improving outcomes of LS.

Graphical abstract

Figure 1.

Description of the cohort and most proximal immunotherapy. (A) CONSORT diagram showing patients with LS identified via multicenter retrospective analysis. (B) Map illustrating countries from which cases of LS were submitted. Quantity of cases reported per country represented by colored shading. (C) Percentage of LS cases reported with baseline cytogenetics incorporating a KMT2Ar (at diagnosis or preimmunotherapy relapse). (D) Summary of most proximal immunotherapy administered before development of LS. (E) Sequencing of various immunotherapeutic agents received. #E-069 and E-080 had blinatumomab and inotuzumab within the same time frame. ∗Indicates when therapy was initiated for post-HSCT relapse. (F) Summary of all antigen-targeted therapies received. ∗Indicates most proximal therapy received, ˆindicates alternative CD19 targeting with an antibody-drug conjugate (ADC). Blina, blinatumomab; HSCT, hematopoeitic stem cell transplant; Ino, inotuzumab; MDS, myelodysplastic syndrome.

Figure 2.

Diagnosis and treatment of LS. (A) Time from the most recent immunotherapy to the development of LS (a single patient who received a CD19-targeted antibody-drug conjugate is not shown here, but this patient developed LS 1.2 months after therapy). Boxes represent median value and upper and lower quartiles with error bars representing the range of reported values. Patient E-069 received inotuzumab and blinatumomab in the same general timeframe but was categorized as inotuzumab being the more recent. (B) Age at initial diagnosis and age at the time of LS. Red indicates those who were diagnosed with infant ALL; green indicates those who were within the pediatric/YA age group; blue indicates those who were aged >39 years at the time of initial diagnosis. (C) Molecular/cytogenetic abnormalities seen before and after LS. (D) Location of LS at time of presentation. YA, young adult.

Figure 3.

Summary of key immunophenotypic, cytogenetic, and molecular changes from baseline to LS. Illustration encompassing all 70 patients with LS including individual patient data. Each column represents an individual participant case. Each row represents a demographic-, treatment-, or disease-related characteristic; some characteristics further divided into rows at baseline (diagnosis or relapse before discovery of LS) and at the time of LS diagnosis. All characteristics are categorical and defined by the colors as described in the figure legend. Immunophenotypic data categorized as not reported/unknown if the flow report was unavailable or if the flow report did not comment on the specific antigen. AYA, adolescent young adult; cMPO, cytoplasmic myeloperoxidase; HSCT, hematopoietic stem cell transplant; LS, lineage switch.

Figure 4.

Post-LS outcomes. (A) First-line treatment approach to LS as reported by treating center. Refer to the supplemental Methods for definitions. (B) Rates of CR to first-line treatment of LS. (C) Percentage who received therapy for LS and achieved a CR at any point. One patient who was lost to follow-up was captured as a nonresponder. (D) Percentage of patients alive or dead at the time of data reporting (∗1 patient did not have sufficient follow-up to determine outcome). (E) Kaplan-Meier curve of OS after the diagnosis of LS for those with follow-up. (F) Swimmer plot depicting the post-LS course of those who were alive at the time of data reporting. AZA, azacitidine; chemo, chemotherapy; CR, complete remission; GO, gemtuzumab ozogamicin; HD, high dose; ID, identity; LD, low dose; VEN, venetoclax.