Phase-2 trial of an intensified conditioning regimen for allogeneic hematopoietic cell transplant for poor-risk leukemia.

Patients with poor-risk leukemia have a high relapse rate despite allogeneic transplant. We report on the phase-2 trial of an intensified allogeneic transplant regimen whose aim was tolerable toxicity and durable remission. Study patients (n=30) had unfavorable first remission cytogenetics, progression from myelodysplasia or active disease due to induction failure or relapse. Conditioning was i.v. BU, targeted to a first-dose plasma area under the curve (AUC) of 700-900 µM min, VP-16 at 30 mg/kg of adjusted ideal body weight and fractionated TBI (FTBI) at 1200 cGy in 10 fractions. GVHD prophylaxis was CsA and mycophenolate mofetil. Regimen-related toxicities (Bearman) included grade II mucositis in 29 patients (97%) and grade III in one patient, grade II-III sinusoidal obstructive syndrome in 2 patients (7%), and grade 2-3 (CTC) skin toxicity in 8 patients (27%). The 30- and 100-day TRMs were 0 and 7% respectively. The median follow-up was 83.7 months (60.7-96.4) for surviving patients. The 5-year overall and disease-free survival was 40% for all patients. Cumulative 5-year relapse incidence (RI) was 23% and TRM was 37%. We have shown promising OS and RI in these poor-risk patients, who typically have few curative options.

Expansion of cytotoxic CD3+ CD56+ cells from peripheral blood progenitor cells of patients undergoing autologous hematopoietic cell transplantation.

Immunotherapy may potentially improve the outcome of autologous hematopoietic cell transplantation (HCT). Poor effector cell proliferation and marginal antitumor activity limit attempts to use immunotherapy. We have characterized the ex vivo expansion, up to 1000-fold, of CD3+ CD56+ lymphocytes from the peripheral blood lymphocytes (PBL) of healthy donors. Expanded cells termed cytokine-induced killer (CIK) cells induce non-major histocompatibility complex-restricted lysis of tumor cells and demonstrate cytolytic activity superior to lymphokine-activated killer cells without the requirement of interleukin (IL)-2 treatment in vivo. To determine whether cytolytic cells could be expanded from patient material, we evaluated samples of peripheral blood progenitor cells (PBPCs) from 25 patients undergoing autologous HCT. The PBPCs were expanded by priming with interferon-gamma followed by anti-CD3 monoclonal antibody and IL-2 the next day. Fluorescence-activated cell sorting analysis was performed on days 0, 15, 21, and 28 of cell culture. The median T-cell content rose from 15.3% (range, 1.1% to 89.7%) on day 0 to 97.2% (range, 83.6% to 99.5%) by day 15. By day 21, T cells expanded 21.8-fold (range, 1.7- to 420.0-fold) and CD3+ CD56+ cells expanded 44.8-fold (range, 5.1- to 747.0-fold). CIK cells were used as effector cells against B-cell lymphoma targets (OCI-Ly8) with a median of 24% (range, 3% to 67%) and 42% (range, 6% to 96%) specific lysis of target cells on days 21 and 28, respectively. CIK cells derived from PBL of 2 additional patients with acute myelogenous leukemia demonstrated 39% and 78% specific lysis of OCI-Ly8 and 26% and 58% specific lysis of autologous leukemic blasts at an effector:target ratio of 40:1. CIK cells may be expanded from granulocyte colony-stimulating factor-mobilized PBPCs of patients undergoing autologous HCT. CIK cells may provide a potent tool for use in posttransplantation adoptive immunotherapy.

High-dose therapy with hematopoietic cell transplantation for patients with central nervous system involvement by non-Hodgkin's lymphoma.

Central nervous system (CNS) involvement by non-Hodgkin's lymphoma (NHL) carries a poor patient prognosis whether it occurs as a primary site of disease or secondarily in patients with systemic disease. In a group of 481 patients undergoing high-dose therapy with hematopoietic cell transplantation (HCT) for NHL, 15 patients (3.1%) were identified with CNS involvement. Two patients had primary CNS lymphoma, and 13 had secondary disease. All patients received intrathecal chemotherapy, and 13 received CNS radiotherapy before transplantation. Fourteen patients received systemic chemotherapy. At the time of transplantation, both patients with primary CNS lymphoma and 8 patients with secondary disease had achieved a complete response, 3 patients had achieved a partial response, 1 had failed induction therapy, and 1 had progression of CNS disease before high-dose therapy. Fourteen patients received carmustine, etoposide, and cyclophosphamide as the preparative regimen, and 1 patient received fractionated total body irradiation instead of carmustine. The 2 patients with primary CNS lymphoma were alive and free of disease, 1 at 1,085 days after HCT and 1 at 3,704 days after HCT. The actuarial 5-year event-free survival (EFS) was 46% +/- 26%, and overall survival (OS) was 41% +/- 28%. The median EFS and OS were 2.2 and 1.5 years, respectively. Three patients experienced symptomatic memory loss or intellectual decline after therapy, 1 patient developed paraplegia, and 1 patient had a thrombotic stroke 20 months after HCT. Despite treatment-related toxicities, 7 patients responding to quality-of-life questions at approximately 1 year after HCT gave their overall quality of life a median rating of 9 out of a possible 10 (range, 6-10). High-dose therapy with autologous HCT can produce extended EFS in patients with secondary CNS lymphoma and possibly in those with primary CNS NHL.