[1646] Clinical Trial of Therapeutic Blockade of CTLA4 with Ipilimumab in Patients with Relapse of Malignancy Following Allogeneic Hematopoietic Transplantation. Session Type: Poster Session, Board #800-I
[This is an abstract relating to a poster presentation at this year's ASH conference. It seems to open up a completely new front in the usage of anti-CTLA4 mAbs.]
Asad Bashey, Bridget Medina, Sue Corringham, Mildred Pasek, Ewa Carrier, Linda Vrooman, Howard Streicher, Israel Lowy, Scott R. Solomon, Lawrence E. Morris, Kent Holland, James R. Mason, Robert J. Soiffer, Edward D. Ball Blood and Marrow Transplant Program, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA; Hematologic Malignancies, Dana Faber Cancer Institute, Boston, MA, USA; Pharmaceutical Management Branch, NCI, Bethesda, MD, USA; Medarex Inc, Bloomsbury, NJ, USA; Scripps Clinic, La Jolla, CA, USA; Blood and Marrow Transplant Group of Georgia at Northside Hospital, Atlanta, GA, USA
Relapse/progression of malignancy (RM) is an important cause of treatment failure and death following allogeneic hematopoietic stem cell transplantation (allo-HCT). CTLA-4 is an important negative regulator of effector T-cell activation. CTLA-4 inhibition has demonstrated potent anti-cancer effects in animal models, and in patients with some solid tumors. CTLA-4 blockade following allo-HCT may potentially augment graft-versus-malignancy but GVHD may also possibly be increased.
We report the safety and preliminary efficacy of a dose-escalation study of a neutralizing human monoclonal antibody targeting CTLA-4 (ipilimumab) in patients with RM following allo-HCT. Eligibility criteria included allo-HCT 90 days previously, > 50% donor T-cell chimerism, no prior grade 3/4 GVHD, no prophylaxis/therapy for GVHD for 6 weeks.
Patients received a single dose of ipilimumab over 90 min. DLI at a dose of 5 x 10e6 CD3 cells/kg was allowed 8 weeks following ipilimumab if no GVHD occurred and RM was present. A total of 29 patients were treated at four centers (23M, 6F; median age 43 (21-65); Hodgkins disease [HD] =14 Myeloma [MM]=6, CML=2, CLL=2, AML=2, NHL=1, Renal Ca =1, Breast Ca=1; 19 related donors, 10 unrelated; 6 myeloablative, 23 RICT).(4 at dose-level 1 [DL1] 0.1 mg/kg, 3 at 0.33 mg/kg [DL2], 4 at 0.66 mg/kg [DL3], 3 at 1.0 mg/kg [DL4] and 15 at 3.0 mg/kg [DL5]). Eight patients had failed prior DLI. Median time between BMT and ipilimumab was 366 d (125-2368).
Dose-limiting toxicity was not encountered. No patient developed clinically significant GVHD within 90 days following ipilimumab alone. Three possible immune adverse events were documented: grade 3 polyarthropathy 14 weeks following ipilimumab, and 6 weeks post DLI, which resolved with corticosteroid therapy, (AML, DL1); grade 1 hyperthyroidism with thyroid-stimulating antibody 6 weeks post ipilimumab (CLL, DL3). Grade 2 pneumonitis responsive to corticosteroids (HD, DL5). Ten patients received DLI after ipilimumab. Three patients developed objective evidence of disease response after ipilimumab alone: PR in a patient with mantle cell NHL lasting 3m [DL4]; ongoing CR in a two patients with HD [DL5].Two of these patients had failed prior DLI. Three additional patients demonstrated possible anti-cancer effects (MR in a HD patient, reduction of PB and BM blasts in AML, DL1; maintenance of molecular remission in a CML patient given ipilimumab alone for 3.5 yrs despite stopping imatinib, DL1).
This study shows that doses of ipilimumab (up to 3.0 mg/kg) can safely be administered to patients with RM following allo-HCT without inducing/exacerbating GVHD while inducing regressions of malignancy including durable CR in some patients.
Abstract #1646 appears in Blood, Volume 110, issue 11, November 16, 2007
Saturday, December 8, 2007 5:30 PM
Session Info: Poster Session: Recurrence, Second Cancer, and Late Complications after Transplantation (5:30 p.m.-7:30 p.m.) |
