Theranostics in Hematooncology

Abstract

In the early 2000s, major clinical trials provided evidence of a favorable outcome from antibody-mediated radioimmunotherapy for hematologic neoplasms, which then led to Food and Drug Administration approval. For instance, the theranostic armamentarium for the referring hematooncologist now includes ⁹⁰Y-ibritumomab tiuxetan for refractory low-grade follicular lymphoma or transformed B-cell non-Hodgkin lymphoma, as well as ¹³¹I-tositumomab for rituximab-refractory follicular lymphoma. Moreover, the first interim results of the SIERRA phase III trial reported beneficial effects from the use of ¹³¹I-anti-CD45 antibodies (Iomab-B) in refractory or relapsed acute myeloid leukemia. During the last decade, the concept of theranostics in hematooncology has been further expanded by C-X-C motif chemokine receptor 4-directed molecular imaging. Beyond improved detection rates of putative sites of disease, C-X-C motif chemokine receptor 4-directed PET/CT also selects candidates for radioligand therapy using β-emitting radioisotopes targeting the identical chemokine receptor on the lymphoma cell surface. Such image-piloted therapeutic strategies provided robust antilymphoma efficacy, along with desired eradication of the bone marrow niche, such as in patients with T- or B-cell lymphoma. As an integral part of the treatment plan, such radioligand therapy-mediated myeloablation also allows one to line up patients for stem cell transplantation, which leads to successful engraftment during the further treatment course. In this continuing education article, we provide an overview of the current advent of theranostics in hematooncology and highlight emerging clinical applications.

Keywords: C-X-C motif chemokine receptor 4; CXCR4; hematooncology; lymphoma; radioimmunotherapy; theranostics.

FIGURE 1.

Structures of established (¹⁸⁸Re-CD66 antibodies, ⁹⁰Y-ibritumomab tiuxetan) and novel (⁶⁸Ga-pentixafor, ⁹⁰Y-pentixather) theranostic agents applied in hematooncology.

FIGURE 2.

Patient with NHL treated with ⁹⁰Y-ibritumomab tiuxetan. (A) Pretherapeutic maximum-intensity projection derived from ¹⁸F-FDG PET revealed multiple lymphoma manifestations in abdomen (arrowheads). (B) PR with inactive disease was achieved as visualized on ¹⁸F-FDG PET at 3-mo follow-up. (Modified from (67).) (C) Response rates of major clinical trials using ⁹⁰Y-ibritumomab tiuxetan (6,22,25) (green indicates disease control depending on study’s definition; red indicates uncontrolled disease).

FIGURE 3.

SUV_max (A) and target-to-background ratios (B) for 690 patients scanned with ⁶⁸Ga-pentixafor PET/CT for assessment of in vivo CXCR4 extent. Black dashed lines show SUV_max of 6 and 12 and target-to-background ratio of 4 and 8, respectively. ALL = acute lymphoblastoid leukemia; BP = blood pool; CCC = cholangiocarcinoma; CLL = chronic lymphocytic leukemia; DSRCT = desmoplastic small round cell tumor; NEN = neuroendocrine neoplasm; NSCLC = non–small cell lung carcinoma; SCLC = small cell lung carcinoma; adrenocortical adenoma = aldosterone-producing adrenocortical adenoma. (Modified from (40).)

FIGURE 4.

CXCR4-targeting ⁶⁸Ga-pentixafor PET/CT for dissecting true relapse and autoimmune-mediated side effects in MM patient scheduled for B-cell maturation antigen–targeting CAR T-cell therapy (idecabtagene vicleucel). (A) Before CAR T-cell therapy, ¹⁸F-FDG showed osseous lesions (arrows). (B) On restaging 3 mo after CAR T-cell therapy, myeloma clearance in skeleton was observed on maximum-intensity projections of ¹⁸F-FDG and ⁶⁸Ga-pentixafor PET. Only ¹⁸F-FDG, however, revealed uptake in pulmonary system; no such radiotracer accumulation was observed on CXCR4-directed imaging. Single-cell RNA sequencing on lung specimen demonstrated upregulation of Th17.1-positive T cells, which are associated with autoimmune diseases such as sarcoidosis. (C) Six months after CAR T-cell therapy, both imaging modalities showed novel manifestations (red box) suggestive of relapse. ⁶⁸Ga-pentixafor PET–guided biopsy was conducted, and single-cell RNA sequencing then revealed malignant plasma cells along with increased CXCR4 expression (leftmost panel in C). CART = CAR T-cell therapy. (Modified from (15).)

FIGURE 5.

MZL patient with additional periorbital disease site (white arrow) identified on ⁶⁸Ga-pentixafor PET/CT. On ¹⁸F-FDG maximum-intensity projection (MIP, left) and transaxial PET/CT (middle, bottom), periorbital manifestation was masked by normal biodistribution in brain. On CXCR4-targeted ⁶⁸Ga-pentixafor (MIP, right; transaxial PET/CT, middle top), this additional site of disease can be identified because of missing brain accumulation. (Modified from (53).)

FIGURE 6.

Patient with MZL and scheduled for rituximab-bendamustine. (A and B) Maximum-intensity projection (A) of ⁶⁸Ga-pentixafor PET revealed multiple lymphoma manifestations, in particular in axilla as seen on transaxial PET/CT (B). (C and D) After treatment, complete remission was achieved on follow-up imaging, indicating that CXCR4-targeted PET/CT may be useful to monitor treatment response. (Modified from (53).)

FIGURE 7.

Patient with relapsed T-cell lymphoma treated with CXCR4-directed RLT and achieving complete remission. (A) Maximum-intensity projection and transaxial ⁶⁸Ga-pentixafor PET/CT at baseline showed extensive disease in skeleton and lymph nodes. Four months after treatment, CR was noted on follow-up ⁶⁸Ga-pentixafor PET/CT. (B) Lactate dehydrogenase as surrogate marker of antilymphoma efficacy peaked directly after RLT and then rapidly declined till conditioning regimen and HSCT, thereby suggesting direct antilymphoma effect caused by CXCR4 RLT. CON = conditioning regimen; LDH = lactate dehydrogenase. (Modified from (7).)

FIGURE 8.

Synergistic effects of radioimmunotherapy and CXCR4-targeted RLT in patient with heavily pretreated diffuse large B-cell lymphoma. (A) Pretherapeutic scintigraphy 24 h after ¹⁷⁷Lu-pentixafor injection revealed multiple disease sites, allowing for calculations of absorbed doses. (B) Baseline maximum-intensity projection and transaxial ⁶⁸Ga-pentixafor PET/CT showed multiple CXCR4-expressing mediastinal and abdominal lesions. (C) ⁹⁰Y-ibritumomab tiuxetan combined with ⁹⁰Y-pentixather was initiated. On ¹⁸F-FDG PET/CT 4 mo later, sites of disease were smaller, indicating PR. (Modified from (63).)