The standardized uptake value calculated from 111In-ibritumomab tiuxetan single-photon emission computed tomography/computed tomography is a useful predictor of the clinical response in patients treated by 90Y- ibritumomab tiuxetan therapy.

90Y-Ibritumomab tiuxetan (IT) therapy is a radioimmunotherapy for indolent B-cell lymphoma. Several predictors of insufficient therapeutic effects have been reported. We performed a retrospective study at a single institute to investigate whether 111In SPECT/CT can predict the therapeutic effects and grade of cytopenia due to 90Y-IT therapy. We enrolled 16 consecutive patients who underwent 90Y-IT therapy, including 15 who underwent 111In-IT SPECT/CT. After 90Y-IT therapy, there were 4 patients in complete remission in whom the lesion SUVmax on 111In-IT SPECT/CT and soluble IL-2 receptor were significantly lower than those of the other patients (P<0.05 and P<0.05, respectively). Based on the log-rank test of factors associated with the progression-free survival (PFS), ≥2 previous treatment regimens was significantly associated with a poor prognosis (P<0.05). The SUV on 111In-IT SPECT/CT may be a good predictor of the clinical response to 90Y-IT therapy.

INTRODUCTION

90Y-Ibritumomab tiuxetan (IT) therapy is a radioimmunotherapy for indolent B-cell lymphoma.- Although 90Y-IT therapy can be safely applied to the elderly or patients with severe complications, there are some cases in which the therapeutic effects are insufficient. Several predictors of insufficient therapeutic effects have been reported,- including tumor diameter and number, clinical stage, number of previous treatment regimens, and maximum standardized uptake value (SUV) calculated from 2-deoxy-2-[F-18]fluoro-D-glucose (FDG) positron emission tomography-computed tomography (PET/CT). 111In-IT scintigraphy is performed to exclude patients who are not eligible for 90Y-IT treatment in whom a higher bone marrow accumulation of 90Y-IT can be expected, followed by severe pancytopenia. On the other hand, the uptake of 111In-IT is also observed in lymphoma lesions; therefore, 111In-IT scintigraphy may be a biomarker to predict the therapeutic effects of 90Y-IT.

At our hospital, whole-body and single-photon emission computed tomography (SPECT)/CT are included in the routine protocol for 111In-IT scintigraphy. SPECT/CT is useful to identify each site with higher radiotracer uptake. In addition, according to previous studies,, SPECT/CT enables the calculation of the SUV, a semiquantitative value that reflects the degree of radiotracer uptake, which is a robust parameter used to compare visual scores and is not influenced by patient factors or the evaluator. Thus, we performed a retrospective study to investigate whether 111In SPECT/CT can be a predictor of the therapeutic effects and grade of cytopenia due to 90Y-IT therapy at a single institute.

PATIENTS AND METHODS

Study design

This retrospective study was approved by the Asahi General Hospital ethics committee and the in-hospital ethical review board prior to its initiation.

Patients

We enrolled 16 consecutive patients who underwent 90Y-IT therapy between January 2017 and October 2019. At our institution, patients who were unable to receive conventional chemotherapy because of their age or complications, or those who refused to receive conventional chemotherapy were indicated for 90Y-IT therapy. The initiation of salvage therapy for indolent B-cell lymphoma was determined by each attending physician.

111In-IT SPECT/CT protocol and image analyses

SPECT/CT images in the thoracic and abdominopelvic region were obtained 48 h following 111In-IT injection (130 MBq) for all patients. Prior to this retrospective study, we performed a phantom study to validate the accuracy of the calculated SUV following a similar method in a previous report. Based on these SPECT/CT images, we calculated the SUV in the lesion with the highest 111In-IT uptake and the mean SUV (SUV) in the BM by placing a globular volume of interest (diameter, 3 cm) in the L1 vertebral body. An example image is shown in Figure 1. For patients who underwent 18F-FDG PET/CT before 90Y-IT therapy, we also calculated the SUV in the lesion with the highest 18F-FDG uptake. We defined the calculated SUV in the lesion with the highest 111In-IT uptake and 18F-FDG uptake as the IT-SUV and FDG-SUV, respectively.

Fig. 1

111In-Ibritumomab tiuxetan SPECT/CT images of a 73-year-old man with recurrent diffuse large B cell lymphoma. An anterior scintigraphic image (a) showing high radiotracer uptake in the left pelvic nodal lesion (black arrow). There was no high uptake in the bone marrow. By placing volumes of interest on fused SPECT/CT images (b and c), the bone marrow SUV and lesion SUV were calculated as 3.21 and 11.37, respectively.

Statistics

The response after 90Y-IT therapy was assessed based on the Lugano Classification. Pearson’s correlation test was used to assess the significance of the correlation between IT-SUV and other values. Welch’s test was used to compare the IT-SUV between patients with a tumor diameter of >50 mm and other patients, the lesion SUV and soluble IL-2 receptor (sIL-2R) between good responders and other patients, and the BM SUV between patients with or without severe cytopenia due to 90Y-IT therapy. Using the Kaplan–Meier method, we created progression-free survival (PFS) curves for patients who achieved stable disease or higher. To identify the optimal cut-off values of the lesion SUV for PFS, ROC analyses were performed. The cut-off value of IT-SUV for PFS was 5.98 (area under curve [AUC] 0.604, 95% confidence interval [CI] 0.245-0.963) and that of FDG-SUV was 9.52 (AUC 0.857, 95%CI 0.604-1). The following prognostic factors were included in the analysis: previous treatment regimen, ≥2; hemoglobin, <12 g/dl; lactate dehydrogenase (LDH), > normal range; sIL-2R, > normal range; number of lymph node lesions, >3; tumor diameter >50 mm; clinical stage, III or IV; Follicular Lymphoma International Prognostic Index (FLIPI), high; complete metabolic response (CMR) achievement; CMR/partial metabolic response (PMR) achievement; IT-SUV, >6; and FDG-SUV, >9.5. The log-rank test was used to compare differences between the survival curves. P-values of <0.05 were considered significant. All statistical analyses were performed using EZR (Saitama Medical Centre, Jichi Medical University, Japan; http://www.jichi.ac.jp/saitama-sct/SaitamaHP.files/statmedEN.html; Kanda, 2012), which is a graphical user interface for the R software program (The R Foundation for Statistical Computing, Vienna, Austria, version 2.13.0).

RESULTS

Patient characteristics

Table 1. summarizes the patients characteristics. The study population included 16 patients (male, n=8; female, n=8), with 15 who underwent 111In-IT SPECT/CT. The median age was 69.5 (range, 56–90) years. Fourteen of 16 patients were diagnosed with follicular lymphoma. The median number of prior regimens was 1 (range, 1–3). The prior regimens of the patients included: rituximab monotherapy (n=6); R-CHOP (n=14), which consists of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone; RB (n=2), which consists of rituximab and bendamustine; EPOCH-R (n=1), which consists of etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, and rituximab; CHOP (n=1); and CVP (n=1), which consists of cyclophosphamide, vincristine, and prednisolone. There were only two patients in whom the diagnosis was confirmed by re-biopsy prior to 90Y-IT therapy. On the evaluation of bone marrow infiltration prior to 90Y-IT therapy, flow cytometry and bone marrow biopsy were performed in all patients, and there were no patients with bone marrow infiltration before 90Y-IT therapy. The reasons why conventional chemotherapy was not available were age over 80 (n=3), low performance status (n=2), and complication of ischemic heart disease (n=1) and collagen disease (n=1). The median FDG-SUV and IT-SUV were 8.225 (range, 2.75–30.49) and 4.35 (range, 0–22.28), respectively. The median BM SUV calculated from 111In-SPECT/CT was 2.81 (range, 1.33–4.46). The median observation period was 344.5 (range, 63–954) days. During this period, 5 patients died; 4 patients died of lymphoma progression and one patient with complete remission of lymphoma died of pneumonia.

Table 1

Patient characteristics (n=16)

	Median (range)
Age at 90Y-IT therapy (years old)	69.5 (56-90)
Male/female	8/8
Performance status (0/1/2)	10/4/2
The diagnosis at the first onset
Follicular lymphoma	14
MALT lymphoma	1
Low grade B-cell, unclassified	1
Number of previous regimens	1 (1-3)
Hemoglobin (<12 mg/dl/other)	7/9
Lactate dehydrogenase (>normal range/other)	7/9
Soluble IL-2 receptor (>normal range/other)	6/10
Clinical stage (I/II/III/IV)	7/5/3/1
Number of lymph node areas (≤3/>3)	9/7
Tumor diameter (≤50 mm/>50 mm)	10/6
FLIPI (low/intermediate/high)	2/6/8
Lesion SUVmax on 18F-FDG PET/CT	8.225 (2.75-30.49)
Lesion SUVmax on 111In-IT SPECT/CT	4.35 (0-22.28)
Bone marrow SUVmean on 111In-IT SPECT/CT	2.81 (1.33-4.46)
Therapeutic effects evaluated by PET
Complete metabolic response	4
Partial metabolic response	5
No metabolic response	3
Progressive metabolic disease	4
Minimum neutrophil count after 90Y-IT therapy (/μL)	603 (57-2526)
Minimum platelet count after 90Y-IT therapy (×104/μL)	5.65 (1.7-22.5)

IT, ibritumomab tiuxetan; MALT, mucosa-associated lymphoid tissue; FLIPI, Follicular Lymphoma International Prognostic Index; SUV, standardized uptake value; FDG, fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; SPECT, single-photon emission computed tomography

Correlation between IT-SUV and other values

There was no significant correlation between IT-SUV and FDG-SUV (R = 0.196, 95%CI -0.37 to 0.658, P = 0.501), LDH (R = 0.176, 95%CI -0.369 to 0.632, P = 0.53), or sIL-2R (R = 0.238, 95% CI -0.312 to 0.669, P = 0.393). In patients with a tumor diameter of >50 mm, the IT-SUV was significantly higher than that of the other patients (p<0.05).

Clinical response of 90Y-IT therapy

After 90Y-IT therapy, there were 4 patients with a complete metabolic response (CMR), 5 patients with a partial metabolic response (PMR), 3 patients with no metabolic response (NMR), and 4 patients with progressive metabolic disease (PMD). Thus, the overall response rate (ORR) and complete response rate (CRR) were 50.0% and 25.0%, respectively.

In patients who achieved CMR, the IT-SUV and sIL-2R were significantly lower than those of the other patients (P<0.05 and P<0.05, respectively) (Fig. 2); however, the FDG-SUV was not significantly lower (P=0.126).

Fig. 2

Comparison between patients who achieved CMR after 90Y-IT therapy and other patients. a The lesion SUV on 111In-IT SPECT/CT (n=15). b Soluble IL-2 receptor (n=16). The numbers below the figure are the mean ± standard deviation. CMR, complete metabolic response; SUV, maximum of standardized uptake value; IT, ibritumomab tiuxetan; SPECT, single-photon emission computed tomography; CT, computed tomography.

The prognostic effects of 90Y-IT therapy

The median PFS was 275 (range, 76-510) days. In the log-rank test, having ≥2 previous treatment regimens was associated with a poor prognosis (P<0.05) (Fig. 3). Patients with an IT-SUV >6 had no significant difference in PFS from the other patients (P=0.103). There were two patients in whom the tumor diameter was >50 mm and the IT-SUV was <6. One patient was in CMR with 90Y-IT therapy and is alive without recurrence at day 667. The other patient was in PMR and was diagnosed with recurrence at day 563.

Fig. 3

Progression-free survival curves for ≥2 previous treatment regimens and others (n=16). Previous Tx, previous treatment regimen.

Toxicities of 90Y-IT therapy

The median lowest neutrophil and platelet counts after 90Y-IT therapy were 603/μL (range, 57–2526/μL) and 5.65 ×104/μL (range, 1.7–22.5×104/μL), respectively. There were 5 patients with a neutrophil count of <500/μL, 7 patients with a platelet count of <5 × 104/μL, and 2 patients with a platelet count of <2.5 × 104/μL. In 2 of the 3 patients older than 80 years of age, the platelet count decreased to <2.5 × 104/μL after 90Y-IT therapy. Granulocyte-colony stimulating factor (G-CSF) was administered to 8 patients, but none underwent platelet transfusion. One patient developed febrile neutropenia and influenza virus infection 21 days after 90Y-IT therapy. In one patient, the number of blood cells decreased again 56 days after 90Y-IT therapy and he was diagnosed with myelodysplastic syndrome. One patient developed pneumonia and died 120 days after 90Y-IT therapy.

In patients with a neutrophil count of <500 μL, the BM SUV calculated from 111In-IT SPECT/CT was higher than that of other patients, but not significantly (P=0.189). Moreover, there was no significant difference in the BM SUV between patients with a platelet count of <5 × 104/μL and other patients (P=0.289).

DISCUSSION

In our study, the IT-SUV was significantly lower in patients who achieved CMR. Of note, a lower IT-SUV was associated with a better response. In a previous study, Hanaoka et al. reported that the IT-SUV in responders and non-responders did not significantly differ. However, similar to our study, the IT-SUV of responders was slightly lower than that of non-responders. The accumulation of 111In-IT may be associated with the tumor cell density and 18F-FDG, thus fewer viable cells in lymphoma lesions may have led to better therapeutic effects. Although it is unknown whether such a phenomenon occurs with other types of radioimmunotherapy, our study may be valuable for predicting the therapeutic effects of radioimmunotherapy.

In our study, there was no significant difference in the FDG-SUV between patients who achieved CMR and those who did not. Tsukamoto et al. reported that the FDG-SUV was an independent prognostic factor. In comparison, our study enrolled a smaller number of patients and their observation period was short. In addition, we were unable to unify the interval between 18F-FDG PET/CT and 90Y-IT therapy due to the retrospective nature of our study. Rituximab therapy was performed between 18F-FDG PET/CT and 111In-IT SPECT/CT for many patients. Rituximab after 18F-FDG PET/CT may have negatively affected the power of PET/CT to predict therapeutic effects.

In previous studies of relapsed refractory low-grade B-cell lymphoma, the ORR and CRR of 90Y-IT therapy were 73–91% and 30–82%, respectively,- whereas in our study, the ORR and CRR were 56% and 25%, respectively. As a reason for the low response, our study included more patients with a poor prognosis than previous studies because the median age of the patients was higher, the number of patients with a high LDH was higher, and half of the patients had a high FLIPI. Furthermore, some patients with transformation of follicular lymphoma may have been included in our study because most patients did not undergo repeated tissue biopsy at the time of lymphoma recurrence to confirm the diagnosis.

In our study, although the high SUV in the BM calculated from 111In-IT SPECT/CT was associated with a high grade of neutropenia, there was no significant difference. One possible reason for this is that the exact lowest neutrophil count was unable to be plotted due to G-CSF intervention in half of the enrolled patients. Regarding thrombocytopenia, two of the three patients aged >80 years developed grade 4 thrombocytopenia after 90Y-IT therapy. Furthermore, 5 of 16 patients had grade 4 neutropenia even though none had bone marrow infiltration before 90Y-IT therapy. In some European countries, 111In-IT scintigraphy is omitted. However, as 90Y-IT therapy is often used for the elderly and patients with complications, it is necessary to discuss whether 111In-IT scintigraphy can be omitted.

The present study has several limitations. First, we were unable to measure the size of each tumor precisely because patients had not undergone contrast-enhanced CT near the time of 111In-IT SPECT/CT. Previous studies reported the tumor diameter as a prognostic factor., To evaluate the prognostic power of IT-SUV, the tumor diameter should be incorporated into the analysis in combination with the IT-SUV data. In our study, there were two patients with a large tumor diameter and low IT-SUV, and they had the most favorable course among our patients; however, no further analysis was possible. Furthermore, we should perform multivariate analysis including LDH, sIL-2R, and the number of previous treatment regimens to confirm whether IT-SUV is an independent prognostic factor. However, due to the small number of patients, only univariate analysis was performed. The second limitation is that we only analyzed the SUV as a SPECT/CT or PET/CT parameter in this study. The SUV only reflects the voxel with the highest radiotracer uptake in the tumor. Thus, it cannot reflect the characteristics in whole lesions or tumor volumes. However, the use of volumetric parameters, such as the metabolic tumor burden, on 18F-FDG PET/CT is not well-established in the field of SPECT/CT, at least 111In-IT studies. The third limitation is that the study population was relatively small. A larger study that simultaneously analyzes the accurate tumor size and In-SUV is required to validate our findings.

In conclusion, the SUV calculated on 111In-IT SPECT/CT may be a good predictor of the clinical response to 90Y-IT therapy. Our study demonstrated that a lower IT-SUV is associated with a better response. Although it is unknown whether this phenomenon is only observed with 90Y-IT therapy, our study may provide valuable information regarding the therapeutic effects of radioimmunotherapy.