Lymphocytic Toxicity in Patients After Peptide-Receptor Radionuclide Therapy (PRRT) with 177 Lu-DOTATATE and 90 Y-DOTATOC

Abstract

Purpose:

Peptide-receptor radionuclide therapy (PRRT) with somatostatin analogs is an efficient new tool in patients with neuroendocrine tumors, with low risk of toxicity. Since lymphocytes express somatostatin receptors, the aim of this study was to evaluate lymphocytic toxicity after PRRT.

Methods:

From May 2005 to May 2007, 16 patients affected by neuroendocrine tumors received PRRT with ⁹⁰Y-DOTATOC (9), ¹⁷⁷Lu-DOTATATE (5), or both (2). Absolute count, percentage of leukocytes and lymphocytes, and lymphoid subsets (B, T, and NK) were tested at baseline and until 90 days after treatment.

Results:

A significant lymphoid toxicity (G2–3), mainly affecting B-cells, was observed. It was particularly evident after ⁹⁰Y-DOTATOC. Toxicity resulted in being transient and resolved completely at the end of the follow-up (90 days).

Conclusion:

Lymphocyte toxicity in PRRT is mainly due to the selective targeting on B-cells. The relative sparing of T-lymphocytes could explain the absence of clinical side-effects in these patients, such as increased risk of infections. These findings open interesting perspectives in the treatment of B-cell lymphoproliferative disorders.

Introduction

Somatostatin receptors are typically overexpressed in many tumors of various origin, and currently, five subtypes (sst_1–5) have been identified and cloned.^1,2 Neuroendocrine, breast, lung tumors, and lymphomas often bear sst₂ receptors. The presence of sst₂ receptors enables the peptide-receptor radionuclide therapy (PRRT) of primary and metastatic lesions by means of the radiolabeled somatostatin analogs, [⁹⁰Y-DOTA⁰, Tyr³]-octreotide or ⁹⁰Y-DOTATOC, and [¹⁷⁷Lu-DOTA⁰, Tyr³]-octreotate or ¹⁷⁷Lu-DOTATATE. The theoretic basis of PRRT is the delivery of radioactivity within the tumor cell, owing to the internalization of the receptor and radiolabeled somatostatin analog complex.

Despite differences in schedules, preliminary results obtained with ⁹⁰Y- or ¹⁷⁷Lu-labeled somatostatin analogs are very encouraging and several studies have reported an overall response rate in up to 30% of the cases, making this treatment a new, efficient tool in the management of patients with inoperable or metastasized neuroendocrine tumours.^3

–6

This approach is considered to be safe, although renal and hematologic toxicity may occur. Based on its physicochemical characteristics, ¹⁷⁷Lu-DOTATATE seems to produce better results, in terms of risk-benefit ratio, and shows lower renal and hematologic burden, due to its higher affinity for sst₂ and the lower energy emission and penetration range of the Lu-177 beta particles (E_max β⁻: 0.497 MeV; R_max95: 2 mm; T_1/2 phys: 6.73 days). ¹⁷⁷Lu-DOTATATE seems to share a better effect on small lesions, compared to ⁹⁰Y-DOTATOC (E_max β⁻:2.28 MeV; R_max95: 11.3 mm; T_1/2 phys: 2.67 days), which, in turn, appears more efficient in larger lesions.^7
–9 However, the patient performance status, the biologic characteristics of the tumor, the extent of liver involvement, and the intensity of octreoscan uptake are crucial for the outcome.¹⁰

As stated before, the kidneys are considered the “critical organs” in PRRT, with an absorbed dose threshold in the range of 23–25 Gy (according to the external radiotherapy studies).^9,11,12 Besides the kidneys, the second parameter to be considered is the bone marrow involvement, with the possible occurrence of acute and late toxicity, particularly after repeated administrations.^5,13 Acute hematologic toxicity is usually mild and reversible, while severe (grade 3–4) toxicity is rare (up to 13% after ⁹⁰Y-DOTATOC and up to 4% after ¹⁷⁷Lu-DOTATATE).⁴ As the number of cycles increases, there is a possibility of mild, but progressive, impoverishment in bone marrow generation capacity, and sporadic cases of myelodysplastic syndromes or even overt acute myeloid leukemia have been reported after PRRT, mainly as personal communications. Therefore, an exact calculation of the incidence of these adverse events is not possible, although the incidence seems not higher than in the normal oncologic population.^4,14

Grade 3–4 lymphocyte toxicity has always been reported in almost 75% of patients, although never extensively studied, since no serious infections had ever been reported in the treated patients. This toxicity was, therefore, considered of minor importance, compared to the previously mentioned events.

Since the 1980s, when somatostatin receptors were found largely expressed in circulating lymphoid cells, several studies have been carried out. Currently, there is evidence that somatostatin can modulate lymphocytic functions via its receptors and is likely to play a role during the development of lymphoproliferative diseases.^15
–17

Given the high frequency of lymphoid toxicity observed after PRRT, the aim of this prospective study was to investigate the intensity and duration of lymphocyte toxicity after PRRT, analyzing the alterations of the subpopulation profile.

Materials and Methods

Patients and treatment

From May 2005 to May 2007, among the 282 patients treated with ⁹⁰Y-DOTATOC and the 334 patients treated with ¹⁷⁷Lu-DOTATATE, according to our protocols, 16 eligible patients (9 women and 7 men), 27–67 years (mean, 52), were consecutively enrolled in this study in order to evaluate the type and duration of lymphocyte toxicity (Table 1).

Table 1.

Patients and Treatment Characteristics

Patient no.	Age	Diagnosis	Radiopeptide	Number of cycles	Cumulative activity (GBq)
1	65	Ileal NET	⁹⁰Y-TOC	3	11.8
2	42	Pancreas NET	¹⁷⁷Lu-TATE	5	26.45
3	42	Prostate NET	⁹⁰Y-TOC	2	7.4
			¹⁷⁷Lu-TATE	2	11
4	59	Unknown origin NET	⁹⁰Y-TOC	2	6.47
5	53	Duodenum NET	¹⁷⁷Lu-TATE	4	25.1
6	49	Pancreas NET	¹⁷⁷Lu-TATE	3	16.18
7	53	Pancreas NET	⁹⁰Y-TOC	3	7.47
8	66	Ileal NET	⁹⁰Y-TOC	3	7.39
9	42	Ileal NET	⁹⁰Y-TOC	2	3.7
10	67	Ileal NET	¹⁷⁷Lu-TATE	3	13.3
			⁹⁰Y-TOC	1	1.48
11	67	Colon NET	⁹⁰Y-TOC	1	2.96
12	52	Ileal NET	⁹⁰Y-TOC	2	5.54
13	53	Ileal NET	⁹⁰Y-TOC	2	5.54
14	27	Pancreas NET	¹⁷⁷Lu-TATE	3	10.36
15	45	Lung NET	⁹⁰Y-TOC	1	2.96
16	40	Pancreas NET	¹⁷⁷Lu-TATE	2	11.1

NET, neuroendocrine tumours; ⁹⁰Y-TOC, ⁹⁰Y-DOTATOC; ¹⁷⁷Lu-TATE, ¹⁷⁷Lu-DOTATATE.

Inclusion criteria were: age between 18 and 75 years; normal baseline absolute leukocyte count [according to National Cancer Institute (NCI) criteria]; no chemotherapy for at least 3 months before PRRT; no previous radiotherapy exposing >25% of the bone marrow; no concomitant hematologic diseases; and no previous PRRT. The study was approved by the ethical committee of our institute. All patients were informed about the nature and aim of this study and signed a written informed consent form specifically designed for this analysis.

Nine (9) patients were treated with ⁹⁰Y-DOTATOC (median number of cycles: 2; range, 1–3) with a median cumulative activity of 5.5 GBq (range, 2.96–11.8 GBq). Five (5) patients were treated with ¹⁷⁷Lu-DOTATATE (median number of cycles: 3; range, 1–5) with a median cumulative activity of 16.28 GBq (range, 9.99–26.45 GBq). Two (2) patients were treated with both radiopeptides, the first (patient 3) with a cumulative activity of 7.4 GBq of ⁹⁰Y- DOTATOC in 2 cycles and 11 GBq of ¹⁷⁷Lu- DOTATATE in 2 cycles, and the second (patient 10) with 1.48 GBq of ⁹⁰Y- DOTATOC in 1 cycle and 13.32 GBq of ¹⁷⁷Lu- DOTATATE in 3 cycles. The median time interval between cycles was 112 days (range, 59–249).

Patients underwent blood sampling in order to analyze absolute and percentage leukocyte and lymphocyte count, as well as absolute lymphocyte subpopulation count [B: CD19–20⁺, T: CD3/CD4⁺, and CD3/CD8⁺; natural killer (NK): CD16⁺CD56⁺] at baseline and at 15, 30, 45, 60, and 90 days after each therapeutic cycle up to the fifth cycle, when performed.

For lymphocyte subpopulation detection, blood was collected in ethylene diamine tetraacetic acid (EDTA) tubes and processed by six-color flow cytometry (FACS-Canto, BD Biosciences, San Jose, CA), using a lyse and wash procedure. Briefly, monoclonal antibodies anti-CD45, CD3, CD4, CD8, CD16⁺56, CD19, and CD20 (all purchased from BD) were incubated with whole blood for 20 minutes, and after red blood cell (RBC) lysis with NH₄Cl, a total of 500,000 events were analyzed. The percentage of CD3⁺CD4⁺, CD3⁺CD8⁺, CD16⁺CD56⁺, and CD19⁺ (or CD20⁺) was calculated with respect to the CD45⁺ cells acquired and multiplied with the absolute white blood cell (WBC) count, assessed with an automated hematology analyzer, to asses absolute values.

Toxicity levels were calculated, according to NCI criteria (CTC Common Toxicity Criteria, Version 2.0 June 1, 1999), as follows:

For leukocyte (cell/mm³) G1: 3999–3000; G2: 2999–2000; G3: 1999–1000; G4 <999; and

For lymphocyte (cell/mm³) G1: 1499–1000; G2: 999–500; G3 <499.

The reference intervals of normality for absolute count of lymphoid cell lines were defined, according to the internal criteria from the hemato-oncology laboratory of our institute, as follows:

B-cells (CD19-CD20): 53–506 cell/mm³;

T-cells (CD3-CD4/CD8): 746–2511 cell/mm³; and

NK-cells (CD56): 29–526 cell/mm³.

Collected data were divided in three groups, according to the number of cycles:

Group 1: follow-up data after the first cycle (n = 16);

Group 2: follow-up data after the second cycle (n = 13); and

Group 3: follow-up data after the third to fifth cycles (n = 9).

Radiopharmaceuticals

DOTATOC ([DOTA⁰,Tyr³]-octreotide, where DOTA is 1,4,7,10-tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid) and DOTATATE ([DOTA⁰,Tyr³-Thr⁸]-octreotide) peptides were purchased from Bachem Labs (Bubendorf, Switzerland). The radioisotopes, ¹⁷⁷Lu and ⁹⁰Y, were purchased from PerkinElmer (Waltham, MA). Labeling and quality control were carried out in our institute, according to a published procedure.^18,19

Statistical analyses

The course of each cellular subgroup (WBC; lymphocites/CD45⁺; B-Cells/CD19–20⁺; T-cells/CD3⁺, and NK-cells/CD56⁺) was monitored. Mean values and their standard deviation were used as descriptive indexes. Further, the percentage of reduction of each lymphocytic subgroup was analyzed. The time trend as percentage reduction was also described and compared for each lymphoid cell subset. Finally, for the B-cell subgroup, data obtained from patients treated with ⁹⁰Y-DOTATOC were compared with those from patients treated with ¹⁷⁷Lu-DOTATATE.

Results

A mild transient toxicity (Grade 1–2) in WBC count was observed in 10 patients (62.5%), while an important, nonhomogeneous lymphocyte reduction (Grade 2–3), was observed in almost all treated patients (14/16: 87.5%) (Table 2). The trend (absolute count and percentage) of overall WBCs showed a delayed nadir 60 days after PRRT, while the time couse for the lymphocytes (total and B-T subpopulations) indicated a premature nadir at the first control, 15 days after PRRT, showing a parallel trend, although with different severity (Fig. 1).

FIG. 1.

Trend of absolute B-cell (CD19-20) and absolute T-cell (CD3) count (mean ± standard deviation). Early toxicity is observed for both subpopulations (nadir at 2 weeks after PRRT), but much stronger for B-cells. This toxicity persisted until the end of the follow-up (90 days), inducing a residual toxicity at the beginning of each new cycle.

Table 2.

Hematologic Toxicity Grade (NCI) and Minimal Lymphoid Subset Counts

Patient no.	Max WBC toxicity grade NCI (AC × 10³)	Max lymph toxicity grade NCI (AC)	Min T-cell count (cell/mm³)	Min B-cell count (cell/mm³)	Min NK-cell count (cell/mm³)
1	2 (2.1)	3 (228)	200	5	23
2	1 (3.3)	2 (800)	410	10	100
3	0 (6.0)	2 (774)	550	18	159
4	2 (2.7)	2 (559)	502	6	51
5	1 (3.3)	3 (368)	286	3	61
6	0 (7.0)	1 (1161)	847	93	220
7	2 (2.9)	2 (754)	504	10	72
8	1 (3.2)	2 (585)	492	3	60
9	1 (3.6)	2 (691)	439	3	42
10	0 (4.9)	2 (710)	520	22	61
11	ND	3 (446)	361	0	75
12	2 (2.2)	3 (402)	357	6	28
13	1 (3.3)	2 (784)	558	0	85
14	0 (12.8)	0 (3570)	1916	184	420
15	1 (3.1)	2 (930)	753	28	47
16	0 (6.3)	2 (548)	361	35	64

WBC, white blood cell; NCI, National Cancer Institute (Common Toxicity Criteria 1999); AC, absolute count; max lymph toxicity, maximal lymphocytic toxicity (CD45); min T-cell count, minimal T (CD3) count; min B-cell count, minimal B (CD19/20) count; min NK-cell count, minimal NK (CD56) count; ND, not done.

While the absolute counts of T-, B-, and NK-cells were all decreased after PRRT, considering the percentage values, NK-cells were fluctuating, T-cells were slightly reduced, and B-lymphocytes were strongly and persistently reduced with time (Fig. 2).

FIG. 2.

Percentage trend of lymphocyte subpopulations after the first 3 cycles of PRRT. Considering the percentage values, NK-cells were fluctuating, T-cells were slightly reduced, and B-lymphocytes were strongly and persistently reduced with time.

WBCs

WBCs showed a progressive, mild reduction over time: Grade 1 on 6 patients, Grade 2 on 4 patients, while 5 patients had no toxicity. Patient 11 was not assessable to WBC, due to missing data at the time of the analysis. WBC toxicity was transient and resolved completely at the end of the follow-up (90 days), with a nadir about 60 days after each cycle.

Leukocyte toxicity seemed be higher in patients treated with ⁹⁰Y-DOTATOC. Although the severity of leucopenia seemed to increase with the cumulative administered activity, probably due to the relatively small sample size, a clear statistical correlation between the two variables could not be found (p = 0.083; Mann-Whitney test). Considering the patients treated with up to 3 cycles, those receiving ⁹⁰Y-DOTATOC showed a Grade 2–3 leukocyte toxicity in the control performed 60 days after the third cycle (Tables 3 and 4).

Table 3.

Toxicity After ⁹⁰Y-DOTATOC

Patient no.	Cumulative activity (GBq)	Max WBC tox grade (NCI)	Max lymph tox grade (NCI)	Max T-cell reduction (%)	Max B-cell reduction (%)	Max NK reduction (%)
15	2.96	1	2	43	84	41
11	2.96	NA	3	50	100	68
12	5.4	2	3	72	97	65
13	5.4	1	2	14	100	0
9	5.5	1	2	63	90	83
4	6.47	2	2	75	95	55
7	7.4	2	2	67	95	51
8	7.4	1	2	50	98	79
1	11.8	2	3	84	97	69

Toxicity levels (NCI criteria) and maximal percentage reduction of lymphoid subset cells after PRRT with ⁹⁰Y-DOTATOC.

WBC, white blood cell; NCI, National Cancer Institute (Common Toxicity Criteria 1999); max lymph tox grade, maximal lymphocytic toxicity grade; NA, not assessable.

Table 4.

Toxicity After ¹⁷⁷Lu-DOTATATE

Patient no.	Cumulative activity (GBq)	Max WBC tox grade (NCI)	Max lymph tox grade (NCI)	Max T-cell reduction (%)	Max B-cell reduction (%)	Max NK reduction (%)
14	9.99	0	0	0	22	0
16	11.1	0	2	0	76	0
6	16.28	0	1	0	0	0
5	25.2	1	3	63	98	55
2	26.45	1	2	NA	NA	NA

Toxicity levels (NCI criteria) and maximal percentage reduction of lymphoid subset cells after PRRT with ¹⁷⁷Lu-DOTATATE.

WBC, white blood cell; NCI, National Cancer Institute (Common Toxicity Criteria 1999); max lymph tox grade, maximal lymphocytic toxicity grade; NA, not assessable.

Peripheral total lymphocytes and subpopulations

Grade 2–3 lymphocyte toxicity was observed after each cycle in 14 of 16 patients, with an early nadir at the first control performed 15 days after therapy, and a subsequent tendency to a slow, partial recovery. As for leukocytes, this toxicity seemed stronger after ⁹⁰Y-DOTATOC, although a clear correlation between administered activity and toxicity grade could not be found (p = 0.532; Kruscal-Wallis test) (Tables 3 and 4).

B-cells (CD19/20⁺)

The CD19/20⁺ showed a strong, early drop in the first and second control 15 and 30 days after PRRT (median percentage of reduction, 67%; range, 48%–88%), with a subsequent slow recovery. Since this reduction did not completely recover at the end of the intercycle period, a residual toxicity at the beginning of the next cycle was always present. In Figure 1, the course of B-cells, according to the reference cycle, is shown.

Comparison ⁹⁰Y-DOTATOC toward ¹⁷⁷Lu-DOTATATE

The drop in B-cells resulted more marked after ⁹⁰Y-DOTATOC (median, 97%; range, 84%–100%) than after ¹⁷⁷Lu-DOTATATE (median, 49%; range, 22%–98%). Figure 3 shows the comparative course of B-cell toxicity after ⁹⁰Y-DOTATOC and ¹⁷⁷Lu-DOTATATE (Wilcoxon signed ranks test; p-value = 0.046 and, therefore, <0.05).

FIG. 3.

B-cells toxicity (CD19-20). The drop in B-cells resulted more marked after ⁹⁰Y-DOTATOC than after ¹⁷⁷Lu-DOTATATE. However, after ¹⁷⁷Lu-DOTATATE, maximal B-cell depletion lasted longer (up to 60 days).

For the above-mentioned analysis, the 2 patients who received both radiopharmaceuticals were not considered. Two (2) patients treated with ⁹⁰Y-DOTATOC (patients 11 and 13) showed a complete, yet transient, disappearance of B-cells, as absolute values, at the control performed 30 days after PRRT (Table 2).

T-cells (CD3⁺)

The absolute T-cell count shows a premature mild reduction as a consequence of total lymphocytic cell reduction (median percentage of reduction, 31%; range, 2%–55%), with a subsequent slow recovery. Since this reduction appeared greater at the second cycle (the maximal reduction was 23% for the first cycle and 48% for the second), this toxicity seems to be correlated with the cumulative activity (Fig. 1). Data of the third cycle were few, and therefore, the analysis resulted in being not statistically significant. Three (3) patients showed a transient raise of CD8 subset that resulted in an inversion of the ratio of CD4/CD8 (data not shown).

NK-cells (CD56⁺)

The NK-cells showed a mild toxicity with a nadir about 15 days after the therapy and a complete recovery within 90 days. None of the studied patients had clinical manifestations or symptoms related to lymphocytic toxicity, such as infectious diseases.

Discussion

PRRT with ⁹⁰Y-DOTATOC or ¹⁷⁷Lu-DOTATATE has proven to be a safe, effective therapeutic strategy in neuroendocrine tumors. Since these radiopharmaceuticals have a relevant renal clearance, the kidneys have always been considered the “critical organs,” and thus, the main research efforts have been directed to the reduction of renal irradiation. However, renal toxicity is not the only aspect to be considered. Usually, mild hematologic toxicity is reported after PRRT and cases of myelodisplastic syndrome or even acute myeloid leukemia are sporadically reported in the literature.^4,20 Lymphocyte toxicity is commonly observed after PRRT, and, being apparently not associated to an increase of infections or other disorders, it has no longer been reported. Anyhow, the frequent lymphocytic reduction observed in these patiens seems to justify an analysis of lymphocyte cell behavior in order to explore the exact nature of this toxicity.

In our study, we observed a mild (Grade 1–2) late toxicity on leucocyte count, which almost completely recovered at the end of the follow-up (90 days). Regarding the lymphocytic subpopulations, we observed an important (Grade 2–3) toxicity (the maximum grade) after PRRT, which involved almost exclusively B-cells and appeared increased after each cycle. As expected, in relation with the more favorable physical properties of ¹⁷⁷Lu in comparison to ⁹⁰Y, the B-cell reduction appeared greater after ⁹⁰Y-DOTATOC than after ¹⁷⁷Lu-DOTATATE. In this respect, we can assume that in a single cell, the fraction of radiation escaping the cell diameter is certainly very high with either radiopeptide, and the greatly higher energy of beta-particles deriving from ⁹⁰Y decay largely overcome those of ¹⁷⁷Lu.

According to other researchers, in spite of the important selective B-cell depletion, we did not observe infectious complications. This finding is consistent with the large experience in patients affected by B-cell lymphoma treated with anti-CD20 mAbs, in whom B-lymphocytes remained nearly undetectable for about 6 months, but no increased risk of infections occurred.²¹ As from these observations, the risk of infection seems to be related to the T and NK levels. In our study, relevant changes of these cell lines did not occur, and only 3 transient cases of CD4/CD8 inversion ratio without complications were observed.

Moreover, the relative resistance of T-cells to PRRT with somatostatin analogs could be explained by their higher expression of sst₃, a subtype of somatostatin receptor for which octreotide has a low affinity.^22,23 In the literature, a relevant variable expression of somatostatin receptors has been identified among lymphoid cell lines of different origin (normal T- and B-cells, myeloma, and leukemic cells), and Tsutsumi et al., in 1997, found sst₂ overexpression in peripheral blood cells from leukemic patients.^24,25 These findings suggested that the receptor-expression pattern in human lymphoid cells could be dependent on their state of activation. Somatostatin, which modulates lymphoid-cell function, could, therefore, play a role during the development of lymphoproliferative diseases.²⁶

The assessment of lymphocyte-cell course after PRRT seemed important in order to determine, in a conclusive way, the exact nature and duration of lymphoid toxicity and whether our patients were posed at risk of infectious complications deriving from the therapy. Moreover, our results opened important perspectives regarding further and possible therapeutic applications of PRRT in lymphoproliferative disorders.

To this respect, it must be mentioned that a complete response in a case of chronic lymphoid leukemia after ⁹⁰Y-DOTATOC was reported and confirmed by immunophenotypic analysis 57 months after therapy.²⁷ Further, objective responses after cold somatostatin analog therapy were also reported in some cases of thymoma, a disease related to lymphoproliferative diseases.²⁸

Despite the small population of this study, our results indicate that PRRT with radiolabeled somatostatin analogs is safe regarding the possible risks deriving from the lymphocyte depletion, namely the risk of infections, and that the lymphocyte subset mainly affected is the B one. The sst₅, sst₂, and sst₃ overexpression on lymphoid cells, particularly on the B subpopulation, appear now an attractive target in the future treatment of lymphoproliferative diseases, such as B-cell leukemias and lymphomas. Recently, some pivotal experiences with “cold” and radiolabeled somatostatin analogs in lymphoproliferative disorders, exploiting the sst₂ and sst₃ overexpression in lymphoid cells, have been carried out. Various results were observed and partial clinical responses were reported in patients affected by relapsed and refractory low-grade non-Hodgkin's lymphoma and cutaneous T-cell lymphomas after somatostatin analog therapy.^27,29
–31 Therefore, the overexpression of sst₂ receptors on B-cells, and their selective depletion after PRRT, is the basis for further investigations addressed at defining the potential of PRRT in highly radiosensitive diseases, such as lymphomas and leukemias.

Conclusions

Despite the small population of this study, our results indicate that PRRT with radiolabeled somatostatin analogs (particularly with ⁹⁰Y-DOTATOC) is safe regarding the possible risk of infections, and that the lymphocyte toxicity is mainly directed to the B-cell subpopulation. The overexpression of sst₂ receptors on B-cells, and their selective depletion after PRRT, is the basis for further investigations addressed at defining the potential of PRRT in highly radiosensitive diseases, such as lymphomas and leukemias.

Footnotes

Acknowledgments

The authors wish to thank Chiara Grana, M.D., Silvia Baio, M.D., and Mr. Giani Bufi for their contribution in the development of the study, and Mrs. Deborah Console for editing the manuscript for this article.

Disclosure Statement

No competing financial interests exist.

References

Patel

, Greenwood

, Panetta

et al.

The somatostatin receptor family [review]

Life Sci, 1995; 57:1249.

Bruns

, Weckbecker

, Raulf

et al.

Characterization of somatostatin receptor subtypes [review]

Ciba Found Symp, 1995; 190:89.

Waldherr

, Pless

, Maecke

et al. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq ⁹⁰Y-DOTATOC. J Nucl Med, 2002; 43:610.

Kwekkeboom

, Mueller-Brand

, Paganelli

et al.

Overview of results of peptide receptor radionuclide therapy with 3 radiolabeled somatostatin analogs [review]

J Nucl Med, 2005; 46,Suppl 1:62S.

Bodei

, Cremonesi

, Grana

et al. Receptor radionuclide therapy with ⁹⁰Y-[DOTA]⁰-Tyr³-octreotide (⁹⁰Y-DOTATOC) in neuroendocrine tumours. Eur J Nucl Med Mol Imaging, 2004; 31:1038.

Kwekkeboom

, de Herder

, Kam

et al. Treatment with the radiolabeled somatostatin analog, [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate: Toxicity, efficacy, and survival. J Clin Oncol, 2008; 26:2124.

De Jong

, Valkema

, Jamar

et al. Somatostatin receptor-targeted radionuclide therapy of tumors: Preclinical and clinical findings. Semin Nucl Med, 2002; 32:133.

Cremonesi

, Ferrari

, Bodei

et al. Dosimetry in peptide radionuclide receptor therapy: A review. J Nucl Med, 2006; 47:1467.

Brans

, Bodei

, Giammarile

et al.

Clinical radionuclide theraphy dosimetry: The quest for the “Holy Grial.”

Eur J Nucl Med Mol Imaging, 2007; 34:772.

10.

Kwekkeboom

, Teunissen

, Bakker

et al. Radiolabeled somatostatin analog [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate in patients with endocrine gastroenteropancreatic tumors. J Clin Oncol, 2005; 23:2754.

11.

National Council on Radiation Protection Measurements. Misadministration of radioactive material in medicine—scientific background. Bethesda, MD: NCRP, 1991; 27.

12.

Bernard

, Krenning

, Breeman

et al. d-lysine reduction of indium-111 octreotide and yttrium-90 octreotide renal uptake. J Nucl Med, 1997; 38:1929.

13.

Valkema

, De Jong

, Bakker

et al. Phase I study of peptide receptor radionuclide therapy with [¹¹¹In-DTPA⁰]-octreotide: The Rotterdam experience. Semin Nucl Med, 2002; 32:110.

14.

Bodei

. Ferone D, Grana CM, et al. Peptide receptor therapies in neuroendocrine tumours. J Endocrinol Invest, 2009; 32:360.

15.

Bhathena

, Louie

, Schechter

et al. Identification of human mononuclear leukocytes bearing receptors for somatostatin and glucagon. Diabetes, 1981; 30:127.

16.

Ferone

, van Hagen

, van Koetsveld

et al. In vitro characterization of somatostatin receptors in the human thymus and effects of somatostatin and octreotide on cultured thymic epithelial cells. Endocrinology, 1999; 140:373.

17.

Van Hagen

, Krenning

, Kwekkeboom

et al. Somatostatin and the immune and haematopoetic system: A review. Eur J Clin Invest, 1994; 4:91.

18.

Paganelli

, Zoboli

, Cremonesi

et al. Receptor-mediated radiotherapy with ⁹⁰Y-DOTA-d-Phe¹-Tyr³-octreotide. Eur J Nucl Med, 2001; 28:426.

19.

Chinol

, Bodei

, Cremonesi

et al. Receptor-mediated radiotherapy with Y-DOTA-dPhe-Tyr-octreotide: The experience of the European Institute of Oncology Group. Semin Nucl Med, 2002; 32:141.

20.

Otte

, Herrmann

, Heppeler

et al. Yttrium-90 DOTATOC: First clinical results. Eur J Nucl Med Mol Imaging, 1999; 26:1439.

21.

Maloney

, Grillo-López

, White

et al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood, 1997; 90:2188.

22.

Cardoso

, el Ghamrawy

, Gautron

et al. Somatostatin increases mitogen-induced IL-2 secretion and proliferation of human Jurkat T-cells via sst3 receptor isotype. J Cell Biochem, 1998; 68:62.

23.

Lichtenauer-Kaligis

, Dalm

, Oomen

et al. Differential expression of somatostatin receptor subtypes in human peripheral blood mononuclear cell subsets. Eur J Endocrinol 2004;150:565. Erratum in: Eur J Endocrinol, 2005; 152:325.

24.

Tsutsumi

, Takano

, Ichikawa

et al. Expression of somatostatin receptor subtype 2 mRNA in human lymphoid cells. Cell Immunol, 1997; 181:44.

25.

Reubi

, Waser

, Horisberger

et al. In vitro autoradiographic and in vivo scintigraphic localization of somatostatin receptors in human lymphatic tissue. Blood, 1993; 82:2143.

26.

Ferone

, Hofland

, Colao

et al.

Neuroendocrine aspects of immunolymphoproliferative diseases [review]

Ann Oncol, 2001; 12,Suppl 2:S125.

27.

Agazzi

, Rocca

, Laszlo

et al.

Is CD20 the only target available for radionuclide therapy in lymphoproliferative disorders?

Eur J Haematol, 2005; 74:450.

28.

Ferone

, van Hagen

, Kwekkeboom

et al. Somatostatin receptor subtypes in human thymoma and inhibition of cell proliferation by octreotide in vitro. J Clin Endocrinol Metab, 2000; 85:1719.

29.

Dalm

, Hofland

, Mooy

et al.

Somatostatin receptors in malignant lymphomas: Targets for radiotherapy?

J Nucl Med, 2004; 45:8.

30.

Keller

, Engel

, Schally

et al. Growth inhibition of experimental non-Hodgkin's lymphomas with the targeted cytotoxic somatostatin analogue, AN-238. Int J Cancer, 2005; 114:831.

31.

Witzig

, Letendre

, Gerstner

et al. Evaluation of a somatostatin analog in the treatment of lymphoproliferative disorders: Results of a phase II North Central Cancer Treatment Group trial. J Clin Oncol, 1995; 13:2012.

Lymphocytic Toxicity in Patients After Peptide-Receptor Radionuclide Therapy (PRRT) with 177 Lu-DOTATATE and 90 Y-DOTATOC

Abstract

Purpose:

Methods:

Results:

Conclusion:

Introduction

Materials and Methods

Patients and treatment

Radiopharmaceuticals

Statistical analyses

Results

WBCs

Peripheral total lymphocytes and subpopulations

B-cells (CD19/20+)

Comparison 90Y-DOTATOC toward 177Lu-DOTATATE

T-cells (CD3+)

NK-cells (CD56+)

Discussion

Conclusions

Footnotes

Acknowledgments

Disclosure Statement

References

B-cells (CD19/20⁺)

Comparison ⁹⁰Y-DOTATOC toward ¹⁷⁷Lu-DOTATATE

T-cells (CD3⁺)

NK-cells (CD56⁺)