CXCR4-directed endoradiotherapy with [177Lu]Pentixather added to total body irradiation for myeloablative conditioning in patients with relapsed/refractory acute myeloid leukemia

Abstract

Rationale: Despite recent advances in the targeted therapy of AML, the disease continues to have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloSCT) remains to be the curative therapy option for fit patients with high-risk disease. Especially patients with relapsed or refractory (r/r) AML continue to have poor outcomes. Myeloablative total body irradiation (TBI) based conditioning can be used in AML patients refractory to multiple lines of standard therapy, but the optimal conditioning regimen remains unclear for patients considered to be chemotherapy- refractory. Feasibility of C-X-C-motif chemokine receptor 4 (CXCR4)-directed endoradiotherapy (ERT) has previously been demonstrated in AML patients with CXCR4 expression on leukemic blasts. Methods: Here, we report on a small cohort of seven AML patients refractory to multiple lines (range 3-7) of therapy, who received CXCR4-directed ERT with [¹⁷⁷Lu]Pentixather in combination with TBI and chemotherapy prior to alloSCT. We report outcomes with a focus on toxicity, engraftment, the impact on the bone marrow (BM) niche and efficacy. Results: In this intensively pre-treated group of patients, promising response (6 out of 7 patients) and engraftment (6 out of 7 patients) rates were observed. Histopathological analysis showed that niche compartments are spared and allow for engraftment to occur despite the combined ERT and TBI conditioning. Conclusion: To the best of our knowledge, we report on the first seven patients who received CXCR4-directed ERT in sequential combination with TBI and chemotherapy, providing an effective, individualized conditioning regimen for intensively pre-treated r/r AML patients.

Keywords: CXCR4; acute myeloid leukemia; allogeneic stem cell transplantation; conditioning regimens; endoradiotherapy.

Figure 1

Treatment schedule. Schematic overview of the conditioning regimen. *Duration of in-patient stay varied based on German Radiation Protection Rules; **For patients with HID/MMUD, immunosuppression was started on day +3 instead. TBI = total body irradiation; alloSCT = allogeneic hematopoietic stem cell transplantation; NUC=nuclear medicine; RAD = radiation oncology; BMT=bone marrow transplantation. (Created in BioRender).

Figure 2

In vivo CXCR4 PET Imaging. Pre-therapeutic PET/CT with the CXCR4 ligand [⁶⁸Ga]Pentixafor to confirm in vivo CXCR4 expression. Patient examples with high (A) and moderate (B) CXCR4 expression on PET-imaging. C) SUVmax from pre-therapeutic CXCR4 imaging, measured at indicated sites. Patients 5 and 7 exhibited CXCR4 positive extramedullary disease. (Created in BioRender).

Figure 3

Pre- and post-therapeutic dosimetry. Pre- and post-therapeutic scintigraphy and SPECT/CT imaging of a 47 year old patient with refractory AML. Pre-therapeutic whole-body scintigraphy at 1 hour post injection (p.i.); 22h p.i.; 48h p.i. and 6 days p.i. (A, from left to right) for dosimetry including fused SPECT/CT (B). Post-therapeutic whole-body scintigraphy at 2 h, 24 h, 48 h and 6 d after administration of 14.4 Gbq [¹⁷⁷Lu]Pentixather (C) and fused SPECT/CT (D).

Figure 4

Multispectral Imaging. Multispectral image of an exemplary BM biopsy before treatment shows a compact infiltrate of CD34 positive AML blasts with reduced trilineage hematopoiesis (A). During aplasia, BM with clearance of AML blasts and markedly reduced trilineage hematopoiesis is detected (B). After engraftment, recovery of the BM microenvironment with normal distribution of hematopoiesis and the hematopoietic niche is shown (C). Granulopoesis is detected by MPO, erythropoiesis by E-cadherin and megakaryopoeisis by CD42b. CD20 highlights B- lymphocytes and CD3 T- lymphocytes. Myeloblasts are marked by CD34.