Priming radioimmunotherapy with external beam radiation in patients with relapsed low grade non-Hodgkin lymphoma

Abstract

Background:

The aim of this study was to evaluate the outcomes of priming salvage radioimmunotherapy (RIT) with a low dose of external beam radiotherapy (EBRT) in patients with relapsed low grade non-Hodgkin lymphoma (LG-NHL).

Methods:

Patients who received salvage RIT with or without 2 × 2 Gy EBRT between March 2009 and February 2013 were retrospectively reviewed at a single institution. Planning target volume (PTV) for EBRT was created by adding a 1–2 cm expansion to the gross tumor volume depending on the anatomical location. Kaplan−Meier method via log-rank was employed to analyze the endpoints freedom from progression (FFP) and overall survival (OS).

Results:

We identified 22 patients who received salvage RIT without chemotherapy with a median follow up of 34 months. Of these, 9 (41%) patients were treated with EBRT immediately prior to RIT, and 13 (59%) received salvage RIT alone. Median FFP was not reached in patients who underwent combination treatment, while it was 9 months for patients treated with RIT alone (p = 0.02). OS for all patients at 36 months was 80.3% with no significant difference between the two groups (p = 0.88). On univariate analysis, the addition of EBRT was associated with improved FFP [hazard ratio (HR) = 4.17; 95% confidence interval (CI), 1.24–19.1; p = 0.02)]. No long term toxicities were reported in both groups.

Conclusions:

RIT outcomes and effects were improved with addition of low-dose EBRT immediately prior to it, in the treatment of relapsed LG-NHL with no additional toxicity. This study is hypothesis-generating and the findings should be validated in prospective studies.

Introduction

Patients with indolent lymphoma represent 35–40% of the non-Hodgkin lymphoma (NHL) population [Armitage and Weisenburger, 1998]. The most prevalent type of indolent lymphoma is follicular lymphoma (FL), which most commonly presents at an advanced stage of disease [Martin et al. 2013]. Although the vast majority of patients with FL will not be cured with initial or subsequent therapy, the advancement of chemotherapy and incorporation of rituximab has greatly improved progression-free survival (PFS) [Van Oers et al. 2010].

Ibritumomab tiuxetan (Zevalin®; Spectrum Pharmaceuticals, Irvine, CA) is a murine anti-CD20 monoclonal antibody conjugated to Yttrium-90 (IT-Y90). It is currently the only available radioimmunotherapy (RIT) drug approved by the United States Food and Drug Administration for the treatment of patients with relapsed or refractory FL. Initial studies demonstrated that IT-Y90 was associated with high overall response rates that reached up to 82% for low-grade lymphoma [Witzig et al. 1999]. Subsequently, its benefit as a consolidation treatment following chemotherapy after the first remission was shown in randomized controlled studies [Morschhauser et al. 2008] and in the setting of relapsed or refractory low grade, follicular, or transformed B-cell NHL [Witzig et al. 2002].

Emerging in vitro data have shown that low-dose radiation (0.5–2 Gy) enhances the level of CD20 expression on the cell surface [Gupta et al. 2008; Singh et al. 2014]. Because the effect of IT-Y90 depends on the surface level of CD20 [Singh et al. 2014], we hypothesized there may be a potential synergy between low-dose radiation therapy and RIT. In this study we evaluated whether patients with relapsed low-grade NHL (LG-NHL) who received low-dose external beam radiotherapy (EBRT) to the involved sites immediately before RIT demonstrated an improved PFS in comparison with those treated with IT-Y90 alone.

Methods

Following institutional review board approval, we retrospectively reviewed the charts of patients who were treated with IT-Y90 at our institution between March 2009 and February 2013. Patients were included in our analysis if they had LG-NHL and relapsed or developed disease progression following initial standard of care therapy. Progression of disease or relapse was determined by imaging, symptom presentation and was confirmed by biopsy as needed. Patients who received IT-Y90 immediately after chemotherapy in the primary or salvage settings were excluded. Charts were reviewed to collect information regarding initial and current histology, grade, Ann Arbor stage, and previous treatments. FLIPI risk group [Solal-Celigny et al. 2004] stratification was based on a score calculation taking into account age, stage, mannequin nodal sites, serum lactate dehydrogenase and hemoglobin levels. Tumor measuring >5 cm was previously used by Burdick and colleagues to define bulky disease and applied the same definition [Burdick et al. 2011]. Though not used in the clinic, for the purpose of comparison with previous studies [Burdick et al. 2011; Smith et al. 2012] and to provide information regarding the extent of disease, Ann Arbor stage was provided at time of relapse in this study.

Radiation technique

As previously published [Witzig et al. 1999], on day one patients received 250 mg/m² of rituximab followed by indium-111 IT-Y90 4 h later. Biodistribution using gamma camera was determined on day 3 or day 4. On day 8 patients received a second dose of rituximab followed by therapeutic IT-Y90. The dose of IT-Y90 was weight-based with a range of 0.3–0.4 mCi/kg and a maximum delivered dose of 32 mCi.

EBRT was used at the discretion of the treating radiation oncologist. If the patient received low-dose EBRT, a computerized tomograph (CT) simulation was performed during initial workup. Gross tumor volume for EBRT was defined as lesions larger than 2.5 cm or gross disease when there is no lesion measuring than 2.5 cm. Planning target volume (PTV) was created by adding a margin of 1–2 cm to the gross tumor volume, depending on the anatomical location. The total dose prescribed was 4 Gy delivered in two fractions over two consecutive days. 3D planning was employed to obtain at least 95% coverage of the PTV. Multiple targets could be treated in the same patient. EBRT was scheduled to be completed the same day as administration of the therapeutic dose of IT-Y90 at day 8.

Follow up

Clinical and imaging follow-up assessments were completed at 2–3 month intervals. Weekly blood counts was obtained for at least 8 weeks after the administration of IT-Y90 and transfusion of blood products was administered as needed. National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 was used to grade hematological toxicity.

All images were reviewed to determine the initial maximum tumor diameter and to assess the treatment effect based on LUGANO criteria for radiological and metabolic responses [Cheson et al. 2014], based on CT scans and positron-emission tomograph (PET)-CT scans, respectively.

Statistical analysis

The primary endpoint for this study was freedom from progression (FFP). Secondary endpoints included overall survival (OS) and treatment toxicity. Outcomes were calculated from the date of therapeutic IT-Y90 administration to event and patients were censored at last follow up or death. The times between initial diagnosis and last relapse before IT-Y90, and between completion of last treatment and time of relapse before IT-Y90 were calculated. FFP was calculated from the date of treatment to the date of progression and OS rates were calculated from date of treatment to the date of last follow up or to the date of death. Statistical analyses were performed using JMP 11 (SAS Institute Inc, Cary, NC, USA). Descriptive statistics were used to summarize the cohort including median and range for continuous variables, or counts and percentages for categorical variables. The Kaplan–Meier (KM) method was used to calculate FFP and OS. The log-rank test was used to test differences between groups and to assess the effect of patient, tumor, and other predictive factors of significance on the end points. A p–value <0.05 was considered statistically significant. Multivariable analysis approaches were not employed given the small number of patients included in the final analysis.

Results

Patient characteristics

A total of 141 patients who received IT-Y90 were reviewed. We identified 22 patients with LG-NHL who were salvaged with IT-Y90 alone without chemotherapy. Of these 22 patients, 9 (41%) were treated with a total of 4 Gy in two fractions immediately prior to RIT-Y90 treatment and 13 (59%) received salvage RIT-Y90 alone. Overall, one patient had marginal zone lymphoma and 21 (95%) patients had low-grade FL. A total of 41% of patients were male and the median age was 68 (46–87). Table 1 provides detailed characteristics for all patients. Tables 2 and 3 provide details for patients salvaged with the addition of low-dose EBRT prior to IT-Y90 and those salvaged with IT-Y90 alone, respectively. Biopsy at time of progression was performed in 18 patients. Patients with no biopsies of primary sites (n = 4) were treated with IT-Y90 alone and they are listed in Table 3 with unknown grade at time of progression. All patients completed a pretreatment with bone marrow biopsy, with only one patient with findings concerning for transformation in bone marrow biopsy only (patient 11 in Table 3). A pretreatment PET scan was obtained in 20 patients except for 2 patients in the combination group. Only three patients had extranodal disease with bone or bone marrow involvement (patients 11, 12, and 16 in Table 3). Prior to the most recent relapse, the median number of previous chemotherapy courses received was 1 (1–5) and four patients received salvage high-dose EBRT. Stages at the time of relapse were: stage I, four patients (18%); stage II, nine patients (41%); stage III, one patient (5%); and stage IV, eight patients (36%). There were two patients with bulky disease in the group that received EBRT and IT-Y90, while there was none in IT-Y90 alone group. The median FLIPI score was 2 (1–5).

Table 1.

Patients characteristics.

Characteristic	IT-Y90 (n = 13)	IT-Y90 + EBRT (n = 9)
Age	68 (46–84)	65 (48–88)
Sex (M/F)	4/9	5/4
Follow up (MO)	31.6 (8.5–70.2)	34.7 (13.7–68.7)
Time from original diagnosis to IT-Y90 treatment (MO)	98.5 (11–167.2)	62.1 (14.2–182.9)
Stage at initial diagnosis	2	1
Stage II	2	1	0.47
Stage III	4	3
Stage IV	5	5
Unknown	2	0
Histology
Histology  FL-grade 1	6	5
FL-grade 2	7	3
MZL-grade 1	0	1
Number of previous chemotherapy courses	1 (1–5)	1 (1–3)
Previous ASCT	0	1
Prior radiation	2	2
Stage at time of relapse	2	2
Stage I	2	2	0.62
Stage II	6	3
Stage III	1	0
Stage IV	4	4
Grade at time of relapse  FL-grade 1	3	4
FL-grade 1	3	4	0.41
FL-grade 2	6	4
MZL-grade 1	0	1
Unknown	4	0
Measurement of largest involved site/node (cm)	3.3 (1.2–5)	3.51 (1.6–9)
FLIPI score at time of treatment	2 (1–5)	3 (1–4)
Number of nodal sites	3 (1–10)	2 (1–6)
LDH	535 (160–906)	482 (424–722)
Hgb (mg/dl)	12.9 (10.9–15.3)	14 (10.8–17)

ASCT, autologous stem cell transplant; cm, centimeter; EBRT, external beam radiotherapy; F, female; FL, follicular lymphoma; FLIPI, follicular lymphoma international prognostic index at time of treatment with IT-Y90; Hgb, hemoglobin; IT-Y90, ibritumomab tiuxetan Yttrium-90; LDH, lactate dehydrogenase level at time of treatment with EBRT; M, male; MO, months; MZL, marginal zone lymphoma.

Table 2.

Patient demographics for patients with relapsed low-grade non-Hodgkin lymphoma salvaged with LD-EBRT prior to IT-Y90.

Pt no.	Age (yr)	Sex	Histology	iS	iG	No. of previous treatment courses	No. of previous chemotherapy courses	Prior ASCT	No. of previous salvage EBRT courses	Interval between initial diagnosis and IT-Y90 (MO)	Interval between completion of last treatment and recurrence (MO)	Interval between completion of last treatment and IT-Y90 (MO)	tS	tG	tFLIPI	LDH (U/L)	No. of nodal sites	Measurement of largest involved site/node (cm)
1	48	M	FL	III	1	1	1	N	0	49	26	32	I	1	1	424	1	1.7
2	88	F	FL	III	2	1	1	N	0	14	7	9	II	1	3	722	2	3
3	64	M	FL	II	2	3	2	N	1	70	35	38	IV	2	3	482	2	9
4	58	M	FL	IV	2	5	3	Y	1	183	51	54	II	2	1	485	2	4.3
5	83	M	FL	IV	1	1	1	N	0	49	17	21	II	1	2	478	3	1.9
6	70	M	FL	III	1	1	1	N	0	46	14	16	I	2	2	457	1	4.2
7	65	F	FL	IV	1	2	2	N	0	62	32	35	IV	2	4	605	6	7.7
8	55	F	FL	IV	1	3	3	N	0	75	5	12	IV	1	3	526	5	3.51
9	82	F	MZL	IV	U	1	1	N	0	77	72	83	IV	U	3	472	4	1.6

ASCT, autologous stem cell transplant; cm, centimeter; EBRT, external beam radiotherapy; F, female; FL, follicular lymphoma; iG, grade of follicular lymphoma at initial diagnosis; iS, Ann Arbor stage at initial diagnosis; IT-Y90, ibritumomab tiuxetan Yttrium-90; LD-EBRT, low-dose external beam radiotherapy; LDH, lactate dehydrogenase level at time of treatment with IT-Y90; M, male; MO, months; MZL, marginal zone lymphoma; N, no; Pt no., patient number; tFLIPI, follicular lymphoma international prognostic index at time of relapse and treatment with IT-Y90; tG, grade of follicular lymphoma at time of relapse and treatment with IT-Y90; tS, Ann Arbor stage at time of relapse and treatment with IT-Y90; U, unknown; Y, yes; Y90, Yttrium-90; yr, years.

Table 3.

Patient demographics for patients with relapsed low-grade non-Hodgkin lymphoma salvaged with IT-Y90 only.

Pt no.	Age (yr)	Sex	Histology	iS	iG	No. of previous treatment courses	No. of previous chemotherapy courses	Prior ASCT	No. of previous salvage EBRT course	Interval between initial diagnosis and IT-Y90 (MO)	Interval between completion of last treatment and recurrence (MO)	Interval between completion of last treatment and IT-Y90 (MO)	tS	tG	tFLIPI	LDH (U/L)	No. of nodal sites	Measurement of largest involved site/node (cm)
10	46	F	FL	IV	2	2	2	N	0	98	29	32	II	2	2	454	5	2.1
11	81	F	FL	III	1	2	1	N	1	108	3	5	IV	2	4	527	10	2.7
12	80	M	FL	IV	2	1	1	N	0	153	71	74	IV	2	5	829	8	1.3
13	68	M	FL	IV	2	1	1	N	0	11	5	20	II	1	2	209	2	5
14	62	F	FL	III	1	1	1	N	0	31	5	6	II	U	2	572	3	1.3
15	63	F	FL	U	2	6	5	N	1	121	0.4	5	III	U	3	633	2	4
16	83	F	FL	IV	2	2	2	N	0	109	17	21	IV	2	4	562	5	4
17	84	M	FL	III	1	3	3	N	0	126	1.2	4	I	1	2	541	1	4
18	68	F	FL	II	2	1	1	N	0	63	18	19	II	2	2	533	1	3.8
19	73	M	FL	IV	1	2	1	N	0	35	13	15	IV	U	2	160	4	U
20	55	F	FL	II	1	1	1	N	0	27	8	11	II	1	1	535	3	1.2
21	82	F	FL	III	1	3	3	N	0	167	4	6	II	U	2	906	2	2.8
22	60	F	FL	U	2	1	1	N	0	46	17	18	I	2	3	500	1	4.8

ASCT, autologous stem cell transplant; cm, centimeter; F, female; FL, follicular lymphoma; iG, grade of follicular lymphoma at initial diagnosis; iS, Ann Arbor stage at initial diagnosis; IT-Y90, ibritumomab tiuxetan Yttrium-90; LDH, lactate dehydrogenase level at time of treatment with IT-Y90; M, male; MO, months; N, no; Pt no., patient number; tFLIPI, follicular lymphoma international prognostic index at time of relapse and treatment with IT-Y90; tG, grade of follicular lymphoma at time of relapse and treatment with IT-Y90; tS, Ann Arbor stage at time of relapse and treatment with IT-Y90; U, unknown; Y90, Yttrium-90; Y, yes; yr, years.

Response assessment

On 3 months follow up imaging, post-treatment responses in patients with low-dose EBRT and RIT-Y90 were complete, partial, stable and progression in 6 (67%), 0 (0%), 2 (22%), and 1 (11%) while in those treated with RIT-Y90 alone it was 6 (46%), 2 (15%), 1 (8%), and 4 (31%), respectively. No statistical significant difference in response rate between the two groups was noted (p = 0.23).

Outcomes

The median follow up for all patients was 34 months. FFP was 54.6% at 12 months, and 31.2% at 24 and at 36 months. The addition of low-dose EBRT prior to IT-Y90 treatment was associated with improved FFP in comparison to patients treated with IT-Y90 alone. Median FFP was not reached in those patients who underwent combination treatment while in those treated with IT-Y90 alone it was 9 months (p = 0.02) (Figure 1). For all patients 12, 24, and 36 months OS was 90.7%, 80.3%, and 80.3%, respectively, with no significant difference between the two groups (p = 0.88) (Figure 2). On univariate analysis, adding low-dose EBRT predicted for better FFP (HR = 4.17; 95% CI, 1.24–19.1; p = 0.02). Other predictors for FFP was stage II versus stage I at time of relapse (HR = 5.66; 95% CI, 0.99–106.7; p = 0.05) (Table 4).

Figure 1.

Freedom from progression for patients who received salvage RIT with or without prior low dose EBRT.

EBRT, external beam radiotherapy; RIT, radioimmunotherapy.

Figure 2.

Overall survival for patients who received salvage RIT with or without prior low dose EBRT.

EBRT, external beam radiotherapy; RIT, radioimmunotherapy.

Table 4.

Factors predicting of FFP.

	Tested group	HR	95% CI	p–value	Comparison group
Time from initial diagnosis to IT-Y90	⩽66 months	0.55	0.18–1.54	0.25	>66 months
No of chemotherapy courses before progression	>1	1.64	0.58–4.72	0.34	1
Stage at time of relapse and treatment	2	5.66	0.99–106.7	0.05	1
	3	18.00	0.65–509.2	0.08
	4	3.33	0.54–63.9	0.22
Grade at time of relapse and treatment	2	1.41	0.44–5.32	0.56	1
	U	1.3	0.25–5.92	0.74
Mannequin number of nodal sites	⩾3	0.58	0.19–1.66	0.31	<3
EBRT*	IT-Y90 alone	4.17	1.24–19.1	0.02	IT-Y90 + EBRT
Largest diameter at salvage	⩾4 cm	1.48	0.50–4.32	0.47	<4 cm
Response to salvage treatment following Y-90 ibritumomab tiuxetan	<CR	1.94	0.66–5.54	0.22	CR

CI, confidence interval; CR, complete response; EBRT, external beam radiotherapy; FFP, freedom from progression; IT-Y90, ibritumomab tiuxetan yttrium-90; U, unknown.

^*EBRT used at salvage time immediately prior to IT-Y90.

Toxicity

Common Terminology Criteria for Adverse Events version 4.0 was used to account for hematological toxicity (Table 5). For patients treated with IT-Y90 and low-dose EBRT the total number of grade ⩾3 toxicities in hemoglobin level, absolute neutrophil counts and platelet counts were 1 (11%), 6 (67%) and 3 (33%) patients, respectively. In patients salvaged with IT-Y90 only, the grade ⩾3 toxicities were 1 (8%), 6 (46%), and 7 (54%), respectively. Only one patient who received salvage IT-Y90 alone developed grade 4 thrombocytopenia and required transfusion. By the end of this study, no patient demonstrated persistent grade ⩾3 toxicity or any secondary malignancy.

Table 5.

Toxicity.^*

Treatment	Y90 ibritumomab tiuxetan with LD-EBRT (n = 9)				Y90 ibritumomab tiuxetan only (n = 13)
Grade	1	2	3	4	1	2	3	4
Hgb	6	0	0	1	7	3	0	1
ANC	0	0	4	2	3	3	6	0
platelets	5	1	2	1	2	3	5	2

ANC, absolute neutrophils count; CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; Hgb, hemoglobin; LD-EBRT, low-dose external beam radiotherapy; Y90, Yttrium-90

^*Grade based on CTCAE version 3.

Discussion

This study is to our knowledge the first to report clinical outcomes for priming low-grade lymphoma with low-dose EBRT immediately prior to the delivery of IT-Y90. In addition to the cytotoxic effects of radiation therapy, our results generate an in vivo hypothesis that EBRT may be utilized in a unique way in combination with RIT. Low-dose EBRT may be sufficient to induce a profound upregulation of CD20 surface expression, which in turn enhances the therapeutic efficacy of IT-Y90 leading to improvements in disease control and as expected OS was not different for this treatment within the short 34 months of follow up.

Prospective clinical trials have established the role of IT-Y90 in relapsed or refractory LG-NHL [Wiseman et al. 2002; Witzig et al. 2002]. In a phase II study, IT-Y90 was administered to 30 patients with relapsed or refractory LG-NHL with mild thrombocytopenia after a median of two previous treatments. The overall response rate was 83% with a 37% complete response (CR) rate [Wiseman et al. 2002]. In a phase III randomized study [Witzig et al. 2002] using IT-Y90 versus single agent rituximab for relapsed or refractory low grade, follicular, or transformed B-cell NHL, IT-Y90 demonstrated a higher overall response rate (80% versus 56%) and CR (30% versus 16%). The median duration of response and time to progression was also higher for IT-Y90, at 14.2 versus 12.1 months and 11.2 versus 10.2 months, respectively, although this was not statistically significant. For all of our patients treated with IT-Y90, the overall response rate was 63% with a CR of 54% and median time to progression of 12 months, which are rates comparable with previously published studies.

LG-NHL is characterized by its known multifocal involvement at disease presentation as well as its radiosensitive characteristics. Historically, treatment of bulky and symptomatic FL with low doses of EBRT has resulted in overall response rates of 82−95% and CR rates of 55−74% [Johannsson et al. 2002; Haas et al. 2003; Luthy et al. 2008]. Given the concern of low response rates in bulky disease to RIT [Gokhale et al. 2005], a combination of RIT with EBRT was previously evaluated. Burdick and colleagues reported outcomes for 11 patients with relapsed or refractory FL with bulky disease [Burdick et al. 2011]. Those 11 patients received EBRT to a total dose of 24 Gy with a median of 32 days prior to IT-Y90. Overall, 2 of the 11 patients required an extended break after EBRT. They reported CR rates of 64% and a median PFS of 17.5 months. In another study by Smith and colleagues, prior to the withdrawal of tositumomab-I131 (T-I131) (Bexxar®; GlaxoSmithKline, Research Triangle Park, NC, USA) from the market in 2014, the same concept of adding EBRT before RIT was tested [Smith et al. 2012]. Smith and colleagues compared the outcomes of 10 patients treated with EBRT to a total dose of 20 Gy in 10 fractions 1 month prior to T-I131 versus 9 patients who received T-I131 alone. Bulky disease (>5 cm) was present in 5 out of 10 patients in the EBRT + T-I131 arm while none of the patients in the T-I131 alone arm exhibited bulky disease. Despite patients in the combination arm presenting with more unfavorable features, those treated with both EBRT and T-I131 had equivalent PFS to those treated with T-I131 alone. In these studies, EBRT was used specifically to improve outcomes in patients with bulky disease and higher doses of radiation were used prior to RIT. Also, EBRT was not coordinated with RIT and there were significant delays between the two treatment modalities.

More recently, radiobiology research has demonstrated that ionizing radiation appears to impact the cellular machinery that regulates CD20 protein expression and trafficking, even at low doses [Gupta et al. 2008; Singh et al. 2014]. Gupta and colleagues showed that there is an increase in CD20 surface levels through redox signaling after exposure of Burkitt lymphoma cell lines to 0.5–2 Gy of radiation [Gupta et al. 2008]. At least a two-fold enhancement in CD20 surface levels was observed within 12–20 h after radiation. Singh and colleagues showed the same two-fold increase in CD20 surface levels, with a maximum level reached 20 h after the delivery of radiation, which was sustained for 36 h [Singh et al. 2014]. At the cellular level, these cells showed more reactive oxygen species and changes in mitochondrial membrane potential, which led to alterations in cellular redox balance and cell death. The percentage of cell death at least doubled when monoclonal anti-CD20 antibodies (rituximab or IT-Y90) were added to cell lines treated with either 0.5 Gy or 1.5 Gy, in comparison with cell lines treated with anti-CD20 antibodies only. This finding indicates that the efficacy of anti-CD20 antibodies depends on the CD20 surface level, and that the enhancement of CD20 surface levels following low-dose radiation could be of clinical implication. Based on these scientific observations, we targeted the active disease site with low-dose EBRT immediately prior to the delivery of IT-Y90, as a primer to enhance its effect based on the biologic properties of ionizing radiation on tumor trafficking of CD20. The dose and timing of EBRT was specifically chosen to synergize with IT-Y90 treatment while minimizing toxicity. The outcome from this study is promising warranting further evaluation in a prospective trial.

Of particular note, the addition of priming low-dose EBRT to IT-Y90 demonstrated minimal toxicity. Prolonged cytopenia is the main profound side effect from treatment with RIT. In a previous study [Witzig et al. 2002] the rates of grade 3 and grade 4 ANC, platelet, and hemoglobin toxicities were 57%, 60%, and 2%, respectively. Nadir levels of cell counts ranged from 4−8 weeks post-treatment. Transition from grade 3 to grade 2 required 1 week whereas recovery from grade 2 required 2–4 weeks. In our study the rates of grade 3 and 4 toxicity for all patients were 9% with anemia, 55% with neutropenia, and 45% with thrombocytopenia. There was no increased toxicity with the addition of low-dose EBRT prior to IT-Y90. Such minimal toxicity from priming EBRT is anticipated to improve the therapeutic ratio of this combination treatment approach.

The decision and selection for radiation was at the discretion of the treating radiation oncologist which might introduce selection bias. Other limitations of our study include its retrospective nature and the small number of patients. Nevertheless, we were able to obtain characteristics of the patients at initial diagnosis and at the time of relapse before RIT administration as well as the evaluation of response based on LUGANO criteria [Cheson et al. 2014] and overall comparable groups. Our study showed an improved time to progression with the addition of priming low-dose radiation immediately prior to IT-Y90 with no added toxicity. Moreover, this clinical outcome is consistent with our scientific rationale to dose and time EBRT immediately prior to IT-Y90 administration in order to utilize surface upregulation of CD20 by EBRT. Our findings suggest a clinical benefit with EBRT and IT-Y90 with a safe toxicity profile. This study warrants further prospective studies to confirm our data.