A Phase I Study Of Myeloablative Radioimmunotherapy Using Iodine-131 Anti-CD45 Antibody Followed By Autologous Stem Cell Transplantation For High-Risk B-Cell and T-Cell Non-Hodgkin Lymphoma and Hodgkin Lymphoma

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.

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).

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).

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.

No relevant conflicts of interest to declare.