Autologous Stem Cell Transplantation in AL-Amyloidosis Following Yttrium-90 Labelled Anti-CD66 Monoclonal Antibody As Sole Conditioning Is Associated with Low Toxicity and Demonstrable Disease Responses

Delayed diagnosis and lack of effective therapies results in the death of approximately 30% of patients with AL-amyloidosis (AL-A) within the first year of diagnosis. Autologous stem cell transplantation (ASCT) remains an important treatment option, resulting in improved organ function and survival in responders, however its utility is restricted due to the substantial toxicity of conventional ASCT conditioning in the vulnerable AL-A population. We report here the use of a monoclonal anti-CD66 monoclonal antibody (Besilesomab)radiolabelled with yttrium-90 (⁹⁰Y-anti-CD66) as the sole conditioning agent prior to ASCT in a phase I study in AL-A patients. The study had full ethical and regulatory approvals (EudraCT 2015-002231-18; ISRCTN 13400668) and comprised 3 ascending radiation activity levels, 30, 40 and 45 MBq per kg body weight, each with 3 patients. Patients entered the study after fulfilling entry requirements and with informed consent. Prior to receiving ⁹⁰Y-anti-CD66, organ dosimetry and biodistribution were determined using anti-CD66 labelled with indium-111 (¹¹¹In-anti-CD66) with sequential gamma camera imaging. Estimated absorbed radiation to critical organs was determined from an established dosimetry model, organ radiation dose expressed in Gray (Gy). Radiation dose limits of 45Gy for the bone marrow, 15Gy for the liver were used as safety measures.

Table 1 summarises patient characteristics, the majority of whom had received multiple lines of treatment including three who had previously undergone ASCT using high dose melphalan (HDM) conditioning. The primary end-point was treatment related toxicity as determined using CTCAE v4.0. Haematological toxicities (cytopenia) were excluded as adverse events (AEs) unless considered life-threatening. Secondary end-points were: clonal disease response determined by changes in serum free light chain assay (FLCa) and malignant plasma cell percentage in bone marrow (BM) as determined by multi-colour flow cytometry; cardiac toxicity using NT-proBNP measurements; overall survival and time to disease progression; biodistribution and dosimetry using SPECT-CT imaging; neutrophil and platelet engraftment (European Blood and Marrow Transplant criteria).

Results: Ten patients were studied with ¹¹¹In-anti-CD66, of whom 9 proceeded to ⁹⁰Y-anti-CD66 conditioning with infused activity determined by study cohort and body weight; one patient failed dosimetry with excessive hepatic uptake and 2 received reduced activity to keep the BM dose within the 45Gy limit. In total 47 AEs were recorded the majority (41) grades 1-2 with no Serious Adverse Events (SAEs); 3 AEs recorded as grade 4; no transplant related deaths and all patients engrafted with median neutrophil recovery by D+13, platelets by D+11. Importantly no patients experienced mucositis or therapy related diarrhoea maintaining oral nutrition. All patients became profoundly cytopenic consistent with bone marrow suppression due to the targeted radiation. Only two patients experienced a fever post-transplant, neither life-threatening. Table 2 summarises the estimated absorbed radiation dose to critical organs and disease responses. Of the 9 patients treated with ⁹⁰Y-anti-CD66 and ASCT, 2 had complete responses (CR) and 5 had partial responses (PR); 1 stable disease and 1 progressive disease determined by FLCa. Six of 8 evaluable patients showed a reduction in percentage of malignant plasma cells in the BM. The study collected data to D+100 post-transplant but 4 patients showed continuing reduction in clonal FLCa beyond D+100 with one achieving a near CR 9 months post-transplant. No dose limiting toxicity was seen. No cardiac AEs were recorded. All patients are alive with median follow-up of 32.8 months (15.3 - 58.4).

Summary: We have demonstrated that ⁹⁰Y-anti-CD66 therapy can be used safely as sole conditioning agent prior to ASCT in pre-treated AL patients, associated with low toxicity and promising disease response rates, including patients who previously had undergone ASCT using HDM. BM radiation doses of up to 45Gy were achieved using this targeted approach with acceptably low doses delivered to other critical organs. Further trials are required to determine the full potential of this agent in the context of stem cell transplantation for AL amyloidosis and other haematological diseases. This research was funded by the charity Blood Cancer UK.

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