Stem Cell Transplantation with ⁹⁰yttrium Ibritumomab Tiuxetan(⁹⁰YIT) in Non-Hodgkin's Lymphoma (NHL): Observations From PET Pre-Treatment Imaging and Responses in Allografted Refractory Follicular Histologies.

Relapse continues to be the primary cause of treatment failure in patients (pts) with NHL undergoing transplantation. We have previously reported the adverse prognostic value of PET+ in autologous transplants (AUTO) and disease refractoriness in pts undertaking a non-myeloablative allogeneic transplantation (NST). In order to improve outcome, we and others have previously established the feasibility of addition of ⁹⁰YIT to the transplant conditioning. Herein, we report the long-tem efficacy of this strategy in 74 pts.

Each pt received a single dose of ⁹⁰YIT (0.4 mCi/kg on day -14) with BEAM as a conditioning regimen in AUTO candidates [relapsed chemosensitive diffuse large cell b-cell (DLBCL); relapsed chemosensitive follicular (FL) if no matched sibling donor was available; mantle cell (MCL) in first remission; age ≤ 65], or with fludarabine, cyclophosphamide and rituximab (Blood 2008:111:5530) in candidates for NST (relapsed chemosensitive or refractory FL and MCL, transformed NHL if not candidates for AUTO, CLL, up to 50% marrow involvement with disease, age ≤ 70).

This cohort included 40 pts (DLBCL=25, FL=11, MCL=3, SLL =1). Median age was 53 (range, 31-65) years. Median prior treatments was 2 (range,1-4). At transplant, 21(52.5%) were in CR, 16 (40%) in PR, and 3 pts (7.5%) with DLBCL had stable disease. Nine pts (22.5%) had elevated LDH and 7 of 38 (18%) were PET +. At study entry, median serum rituximab level was 5mcg/ML (range, 0-56.4), and soluble CD20 serum level was 457 nM/L (range, 20.7-1501). Adverse events were similar to those with BEAM alone, and 4 pts (10%) developed secondary malignancies. Median time to >ANC 500 was 9 (range, 7-12) days and to platelet >20,000/mm³ was 11 (range, 2-90) days. At a median follow-up time of 3.6 (range,1.4 - 4.9) years, the 3-year overall (OS) and progression-free survival rates (PFS) were 78% and 64%, respectively. We were not able to identify important determinants of outcome; this included PET+, serum rituximab and soluble CD20. Although histology had no statistically significant impact, a persistent pattern of relapse over time was observed in FL (PFS at 1-,2- and 4-year were 91%, 64% and 45%, respectively), whereas a plateau was observed in DLBCL at 24 months (PFS of 76%). This cohort included 34 pts (FL=11, CLL=20, DLBCL=2, MCL=1). Median age was 59 (range, 29-70). Eight of the 11 pts with FL had high [n=6 (55%)] or intermediate [n=2 (18%)] FLIPI at study entry; 8 (73%) were PET+, and 6 (55%) had refractory disease (non-responding or progressing to at least two lines of therapies such as R-CHOP or RICE). Seven pts with CLL (35%) had refractory disease; 10 of 16 (62.5%) had unmutated IgVH, and 5 of 14(36%) had p53 mutation. Peripheral blood from HLA-compatible sibling donors was the source of graft in all pts. Tacrolimus and methotrexate were used for GVHD prophylaxis. Median time to ANC >500 was 11(range, 8-17) days, and to platelets > 20,000/mm³ was 10 (range, 0-55 days). Median donor T cells at days 30 and 90 were 90% and 100%, respectively. Cumulative incidence (CI) of acute II-IV GVHD was 32% (none had grade 3, one had grade IV), and the CI of extensive chronic GVHD was 44%. With a median follow-up time of 22 (range, 3-73) months, the PFS rates at 3-year for FL and CLL were 100% and 37%, respectively. The causes of failure in CLL were progression (n=6) and complications related to chronic GVHD (n=2).

These data provide evidence that combining ⁹⁰YIT at 0.4mCI/kg with the conditioning improves outcomes in NHL pts undergoing AUTO or NST, but not in CLL. Our results also represent the first report showing that the combination may overcome the negative prognostic value of PET+ in NHL, and that the addition of ⁹⁰YIT to NST conditioning can induce long-term remission in relapsed refractory FL without added toxicity. Verification of our results in a larger cohort of pts is highly warranted.

Khouri:BiogenIDEC: Research Funding. Off Label Use: The use of 90Yttrium Ibritumomab Tiuxetan in stem cell transplantation.