Abstract

Background

High-dose therapy and autologous stem cell transplant (ASCT) remains the standard of care for many high-risk/relapsed B-cell non-Hodgkin lymphomas (B-NHL), T-cell NHL (T-NHL) and classical Hodgkin lymphoma (HL), yet most will not achieve sustained remissions. High-dose anti-CD20 radioimmunotherapy (RIT) and ASCT has been successfully employed to address this challenge in B-NHL, yet relapse still occurs potentially due to blockade of target sites by circulating rituximab (R). RIT options are limited for patients with T-NHL and HL. Preclinical data indicate that targeting the panhematopoietic antigen CD45 with RIT can successfully circumvent R blocking in B-NHL and target a variety of T-NHL histologies (Gopal, 2008 & 2009). We thus performed a phase I trial using high-dose anti-CD45 RIT and ASCT for B-NHL, T-NHL, and HL.

Methods

Patients were ≥18 years old with relapsed, refractory, or high-risk B-NHL, T-NHL, or HL and had acceptable organ function with an ECOG performance status of 0-1 and no detectible human anti-mouse antibodies. They could not have received ≥20 Gy of prior radiation (RT) to critical organs or prior ASCT within 1 year, or prior allogeneic transplant at any time. All patients first received anti-CD45 antibody (BC8) trace-labeled with 131I followed by gamma camera imaging to evaluate biodistribution and estimate organ-specific absorbed doses. Patients then received 131I-BC8 at an absorbed dose determined by the following: Patients with prior RT >20 Gy or prior ASCT started at 10 Gy to the dose-limiting normal organ (Arm A), while others started dose escalation at 20 Gy (Arm B). Subsequent dose escalation/de-escalation followed a two-stage approach (Storer, 2001). ASCT occurred after sufficient radiation decay, and G-CSF was started on day 1. Dose limiting toxicity (DLT) was determined by Bearman grade III/IV events. The primary objective was to estimate the maximum tolerated dose, defined as that yielding a DLT rate of 25%. Responses were scored using standard criteria (Cheson, 2007).

Results

Between August 2009 and March 2013, 15 patients were treated. Median age was 62 years (range 20-71); stage III/IV = 11 (73%); median prior regimens = 3 (range 2-12), including 1 prior ASCT; chemorefractory disease (i.e., <PR to the most recent chemotherapy) = 8 (53%); histologies were HL (n = 6), B-NHL (n = 6), and T-NHL (n = 3; see Table). The mean administered 131I activity was 646 mCi (range 344-1064 mCi; 23.9 GBq, range 12.7-39.4 GBq). The liver was the dose-limiting normal organ in 12 patients (2.41-3.98 cGy/mCi). The absorbed dose was escalated to 14 Gy for patients in Arm A (n = 3) and 30 Gy in Arm B (n = 12). Neutrophil (>500/μl) and platelet (>20 K/μl) engraftment occurred a median of 8 (range 10-20) and 12 (range 8-26) days after ASCT, respectively. No DLTs, non-relapse deaths, or non-hematologic toxicities > NCI-CTCAE v3 grade 3 have been observed. Currently, 11 (73%) patients are alive and 7 (47%) are progression-free with a median follow-up of 12 months. Seven (54%) of 13 patients with measurable disease at enrollment had objective disease responses, including 3 of 3 with T-NHL, 3 of 6 with HL, and 1 of 1 with follicular lymphoma (FL; see Table).

Table

Patient characteristics, dose escalation, and response.

Dx Age # of Prior Tx Prior ASCT or RT >20 Gy? Measurable Disease? Activity Delivered Max dose to normal organ (Gy) 1-Month Response 
      mCi GBq   
MCL 64 425 15.7 10 CR 
MCL 59 396 14.6 12 SD 
HL 52 819 30.3 20 CR 
HL 29 344 12.7 50* CR 
AITL 62 825 30.5 22 CR 
HL 20 468 17.3 50* PR 
HL 66 461 17.0 50* SD 
HL 51 12 593 21.9 14 SD 
PTCL 69 814 30.1 24 CR 
10 DLBCL 69 596 22.0 24 SD 
11 AITL 56 642 23.8 24 CR 
12 MCL 71 774 28.6 26 PD 
13 MCL 62 713 26.4 26 CR 
14 FL 67 752 27.8 28 CR 
15 HL 38 1064 39.4 30 SD 
Dx Age # of Prior Tx Prior ASCT or RT >20 Gy? Measurable Disease? Activity Delivered Max dose to normal organ (Gy) 1-Month Response 
      mCi GBq   
MCL 64 425 15.7 10 CR 
MCL 59 396 14.6 12 SD 
HL 52 819 30.3 20 CR 
HL 29 344 12.7 50* CR 
AITL 62 825 30.5 22 CR 
HL 20 468 17.3 50* PR 
HL 66 461 17.0 50* SD 
HL 51 12 593 21.9 14 SD 
PTCL 69 814 30.1 24 CR 
10 DLBCL 69 596 22.0 24 SD 
11 AITL 56 642 23.8 24 CR 
12 MCL 71 774 28.6 26 PD 
13 MCL 62 713 26.4 26 CR 
14 FL 67 752 27.8 28 CR 
15 HL 38 1064 39.4 30 SD 
*

Dose limited to 50 Gy to marrow

Abbreviations not used in text: Dx = diagnosis, Tx = treatments, MCL = mantle cell lymphoma, AITL = angioimmunoblastic T-cell lymphoma, PTCL = peripheral T-cell lymphoma, DLBCL = diffuse large B-cell lymphoma

Conclusion

Myeloablative doses of 131I targeted to CD45 are safe and feasible in patients with lymphoma, with no DLTs observed after delivery of up to 30 Gy to the liver. Objective disease responses in heavily-treated B-NHL, T-NHL, and HL were observed. This work has led to current studies using yttrium-90 as the therapeutic radionuclide (given its longer beta pathlength and absence of gamma emission) in anti-CD45 RIT for lymphoma.

Disclosures:

No relevant conflicts of interest to declare.

Author notes

*

Asterisk with author names denotes non-ASH members.