The Addition of Ibritumomab Tiuxetan (IT) to the ATG/TLI Preparative Regimen Is Safe and May Enhance Post-Transplant Response and Outcomes for Patients with Relapsed or Refractory B Cell Non-Hodgkin Lymphomas
Authors: Cardenas Michael Low , Abedi Mehrdad , Romo Christina , Richman Carol M. , Daly Megan , Tuscano Joseph 
Published: November 2019

Background:

Nonmyeloablative allogeneic stem cell transplantation (NMT) is an effective salvage therapy in relapsed or refractor non-Hodkgin's lymphoma (R/R NHL) but is limited by significant transplant-related mortality (TRM). Total lymphoid Irradiation (TLI) and anti-thymocyte globulin (ATG) conditioning is well tolerated with low TRM and results in significant anti-tumor activity with low rates of graft versus host disease (GVHD). However durable remissions are limited to patients in remission at the time of transplant. We hypothesized that when IT is added to ATG/TLI conditioning this would convert patients (Pts) with stable disease/partial response (SD/PR) to partial response/complete response (PR/CR) and result in improved outcomes after ATG/TLI conditioning and allogeneic transplantation.

Methods:

In this phase 2 study, Pts with CD20+ R/R NHL underwent NMT using G-CSF mobilized peripheral blood stem cells from an HLA-matched (9/10 or better) donor. Included in the category of CD20+ R/R NHL were follicular grade I, II, III (FL), marginal zone, mantle cell (MCL), diffuse large B cell (DLBCL), small lymphocytic lymphoma for which standard curative therapy does not exist or is no longer effective. To be eligible patients had to be older than 18 years of age with Karnofsky performance status (KPS) of ≥ 60.. Patients must have had at least one prior chemotherapeutic regimen and have had anything less than a CR (PR, SD or progressive disease) to their last regimen. Conditioning consisted of rituximab (250 mg/m2, days -21 and -14), IT (0.4 mCi/ kg, day -14), TLI and ATG (800 centigray in 10 fractions and 1.5 mg/kg, respectively, from days -11 to -1). GVHD prophylaxis consisted of cyclosporine (6.25 mg/kg po bid, days -3 to +56 followed by taper) and mycophenylate mofetil (15 mg/kg po, days 0 to +28).The primary endpoint was response conversion rate (SD/PR to PR/CR) monitored with Simon's optimal 2 stage design. Response was assessed by CT or PET/CT at 60 days post-transplant and then every 4 months per International Workshop Lymphoma Response Criteria. Secondary endpoints were time-to-chimerism, 2-year (2Y) overall survival (OS) and event free survival (EFS), toxicity assessment, and GVHD incidence. Time-to-event endpoints were estimated by the Kaplan- Meier method. Toxicities were graded according to the NCI CTCAE v4.0.

Results:

Sixteen Pts were enrolled. Fifteen Pts underwent NMT and are evaluable for toxicity. One Pt died prior to conditioning. Eleven Pts had at least day +60 response assessment and are evaluable for efficacy. One Pt died after transplant but prior to day +60. Three Pts have yet to reach day +60.The average age at transplantation was 61 years (range 30 - 77). The median KPS was 90 (range 80 - 100).The subtypes of R/R NHL among evaluable Pts were FL, DLBCL, MCL, and primary mediastinal B-cell lymphoma (6 Pts, 6 Pts, 2 Pts, and 1 Pt, respectively).Of the 11 Pts evaluable for efficacy, the response conversion rate was 82% (9/11 Pts) with 73% having CR (8/11 Pts). Three Pts had PR prior to achieving CR. The mean duration of CR was 17.0 months. Mixed or full chimerism was demonstrated in 10/11 Pts with 7 Pts achieving full chimerism with the median times to mixed and full chimerism being 31 days and 60 days, respectively. The 2Y EFS and OS were 71% (95% CI ± 29%) and 75% (95% CI ± 25%), respectively. Four Pts had acute GVHD (2 Pts each with Grade (G) 1 and G3). Five Pts had chronic GVHD (3 Pts with limited- and 2 Pts with extensive stage). Of the 15 Pts evaluable for toxicity, 4 Pts developed G2 mucositis or nausea. Two Pts developed G3 febrile neutropenia. Five Pts developed infections (1 Pt with RSV B, 1 Pt with C. diff and folliculitis, 1 Pt with CMV viremia, influenza A, and oral candidiasis, and 2 Pts with oral candidiasis only). Four Pts developed G4 anemia, 6 Pts developed G3-4 thrombocytopenia. One Pt had G3 bilirubin elevation. Expected transplant-related cytopenias occurred 15/15 Pts.

Conclusions:

IT plus TLI/ATG conditioning is well tolerated, had a conversion rate and 2Y EFS of 82% and 71%, respectively which is promising considering this is a heavily pre-treated and mostly refractory patient population. While the results are preliminary and the sample size is small, this regimen warrants further study in larger clinical trials.

Disclosures

Abedi: Abbie: Speakers Bureau; Takeda: Speakers Bureau; BMS: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Speakers Bureau. Daly:Genentech: Research Funding. Tuscano:Takada: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Seattle Genetics: Honoraria; Amgen: Honoraria; Pharmacyclics: Research Funding; Spectrum: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Research Funding.

OffLabel Disclosure:

Ibritumomab tiuxetan (Zevalin)is a CD20-directed radiotherapeutic antibody administered as part of the Zevalin therapeutic regimen indicated for the treatment of patients with relapsed or refractory, low-grade or follicular B-cell non Hodgkin'slymphoma(NHL)previously untreated follicular NHL who achieve a partial or complete response to first-line chemotherapy. We hypothesized that when ibritumomab tiuxetan is added to ATG/TLI conditioning in nonmyeloablative allogeneic stem cell transplantation this would convert relapsed NHL patients in stable disease/partial response to partial response/complete response and result in durable remissions without increasing toxicity.