Radioimmunotherapy with Radretumab in Patients with Relapsed Hematologic Malignancies

Eligibility for R-RIT

High, selective tumor uptake of radretumab (Fig. 1) was observed in 11 of 15 lymphoma patients, including 9 of 11 HL and 2 of 4 B-cell NHL patients; these patients were therefore considered eligible for R-RIT. Two NHL and 1 HL patients exhibited moderate tumor uptake, and no radretumab uptake was found in only 1 patient (HL). In the MM patients (who had no evidence of extramedullary involvement), diffuse radretumab uptake was exclusively found in the BM, resulting in a BM-to-muscle uptake ratio of 2.5 in 2 MM patients, which was considered sufficient for subsequent R-RIT.

Provisional Organ Exposure Estimated with 185 MBq of ¹³¹I-L19SIP

Dosimetric estimates for normal organs and tumor lesions were extrapolated to an activity of 3.7 GBq on the basis of the 185-MBq ¹³¹I-L19SIP data (Fig. 2; Table 1; Supplemental Table 2). In all patients except one, the estimated BM and other healthy-organ absorbed radiation doses were within organ safety thresholds. The provisional radiation doses to lymphoma target lesions were quite heterogeneous, ranging between 0.56 and 76 Gy among patients and between 3.7 and 20.7 Gy in a single patient.

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FIGURE 2.

Radiation-absorbed doses (in Gy) estimated for ¹³¹I-L19SIP administered at activities intended for R-RIT (minimum and maximum values indicated by bars). LLI = lower large intestine; ULI = upper large intestine.

Efficacy of R-RIT

The 10 eligible lymphoma patients received R-RIT at an activity of 3.7 (n = 7), 5.55 (n = 2), or 1.85 GBq (patient 18, dose reduction for low body weight). Two MM patients were treated with R-RIT at 3.7 GBq and 1.85 GBq (dose reduction for preexisting grade 1 thromboleukopenia), respectively. Eight patients received 1 R-RIT administration, 3 received 2, and 1 received 5 (3.7 GBq in all cases). Repeated treatments were followed by separate efficacy evaluations, thus making a total of 19 R-RIT administrations available for efficacy assessment.

Patients’ response to R-RIT is reported in Table 2. R-RIT induced complete response (CR) after the first administration in the diffuse large B cell lymphoma (DLBCL) patient, after both the first and the second administrations in HL patient 5, and only after the second administration in HL patient 12. In all 3 patients, CR was ascertained by complete disappearance of ¹⁸F-FDG–avid disease (Fig. 3). Two rapidly progressive patients experienced a PR 1 mo after R-RIT; however, progressive disease (PD) recurred 4–6 wk thereafter.

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FIGURE 3.

CT (left), SPECT (A center) and PET (B and C center), and SPECT/CT (A right) and PET/CT (B and C right) transaxial ¹³¹I-L19SIP and ¹⁸F-FDG PET/CT sections of DLBCL patient 17: high ¹³¹I-L19SIP uptake in left inguinal lymphoma after R-RIT (A) and at site of hypermetabolic lesion (B) and complete disappearance of ¹⁸F-FDG–avid disease after R-RIT (C).

Objective responses after R-RIT were observed in lymphoma patients with provisional doses to the target lesions exceeding 10 Gy (Table 1). In patients with CR or PR, a high provisional radiation dose to target lesions was found (20.7–76.7 Gy; Table 1). The largest completely disappearing lymphoma lesion after R-RIT was 55 mm in the longest diameter. Objective responses in bone lymphoma lesions were not observed, although transient reduction of ¹⁸F-FDG uptake was detected, associated with symptom relief. Patients progressing after R-RIT still had tumoral uptake of radretumab in subsequent scans, and the level of response to repeated R-RIT was not inferior to that observed after the first administration, except when bone was involved.

The duration of R-RIT–induced responses was 2–7 mo, although CR in the DLBCL patient has been ongoing for 15 mo (Table 2; Fig. 3). Repeated R-RIT administrations extended the clinical benefit, and in 1 HL patient the disease could be controlled for 24 mo with 5 R-RIT administrations (Fig. 4). Both MM patients treated with R-RIT achieved stable disease lasting for 5 and 2 mo (13% and 23% reductions in paraprotein serum levels, respectively).

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FIGURE 4.

Series of ¹⁸F-FDG PET maximum-intensity-projection images taken from HL patient 5 before and after each of 5 subsequent R-RIT administrations (RIT-1 to -5) at activity of 3.7 GBq. CR was achieved after RIT-1 and RIT-2, PR was achieved after RIT-3 and RIT-4, and PD was achieved after RIT-5 (new lesions) associated with some local response.

Safety and Tolerability

After radretumab at 185 MBq, in 1 patient a grade 3 increase in alanine aminotransferase serum levels related to septic fever–induced rhabdomyolysis and in another patient a grade 3 hypopotassemia caused by prolonged grade 1 diarrhea were recorded. Both events were considered unrelated to radretumab.

R-RIT was well tolerated, even when given repeatedly. Grades 3–4 thrombocytopenia occurred in 5 patients after the first R-RIT, starting between day 22 and 41 after radioimmunotherapy and lasting for 4–21 d. Median time to platelet (<100 × 10⁹/L) and neutrophil nadirs was 43 d (range, 25–56 d) and 44 d (range, 43–54 d), respectively (Supplemental Fig. 2). One HL patient had grades 3–4 thrombocytopenia after 5.55 GBq of R-RIT, lasting for 129 d. However, no platelet transfusions were required. Another HL patient had prolonged thrombocytopenia after repeated R-RIT at 3.7 GBq. She eventually developed secondary leukemia and died shortly thereafter. No correlation between hematologic toxicity and BM or whole-body radiation-absorbed dose was found (data not shown).

Although we did not analyze human serum for formation of humoral responses against radretumab, none of the patients receiving repeated R-RIT administrations experienced clinical adverse events possibly caused by the formation of antiradretumab antibodies.