Janet Brunner

A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing.

Studies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 × 10(8)/kg of T cells resulted in consistent engraftment, immune reconstitution, and acceptable rates of GVHD. Cumulative incidences of grade III-IV GVHD, nonrelapse mortality (NRM), and relapse-related mortality were 7.4%, 22.2%, and 29.6%, respectively. With a follow-up of 28-56 months, the 3-year probability of overall survival for the whole cohort is 48% and 75% in patients without disease at HSCT. In the context of CY tolerization, a high, fixed dose of haploidentical T cells was associated with encouraging outcomes, especially in good-risk patients, and can serve as the basis for further exploration and optimization of this 2-step approach. This study is registered at www.clinicaltrials.gov as NCT00429143.

Activity of single-agent melphalan 220-300 mg/m2 with amifostine cytoprotection and autologous hematopoietic stem cell support in non-Hodgkin and Hodgkin lymphoma.

Summary:High-dose chemotherapy using melphalan (HDMEL) is an important component of many conditioning regimens that are given before autologous hematopoietic stem cell transplantation (AHSCT). In contrast to the situation in myeloma, and to a lesser degree acute leukemia, only a very limited published experience exists with the use of HDMEL conditioning as a single agent in doses requiring AHSCT for lymphoma, both Hodgkin lymphoma (HL) and especially non-Hodgkin lymphoma (NHL). Thus, we report results of treating 26 lymphoma patients (22 with NHL and four with HL) with HDMEL 220–300 mg/m2 plus amifostine (AF) cytoprotection and AHSCT as part of a phase I–II trial. Median age was 51 years (range 24–62 years); NHL histology was varied, but was aggressive (including transformed from indolent) in 19 patients, indolent in two patients and mantle cell in one. All 26 patients had been extensively treated; 11 were refractory to the immediate prior therapy on protocol entry and two had undergone prior AHSCT. All were deemed ineligible for other, ‘first-line’ AHSCT regimens. Of these 26 patients, 22 survived to initial tumor evaluation on D +100. At this time, 13 were in complete remission, including four patients who were in second CR before HDMEL+AF+AHSCT. Responses occurred at all HDMEL doses. Currently, seven patients are alive, including five without progression, with a median follow-up in these latter patients of D +1163 (range D +824 to D +1630); one of these patients had a nonmyeloablative allograft as consolidation on D +106. Conversely, 14 patients relapsed or progressed, including five who had previously achieved CR with the AHSCT procedure. Two patients, both with HL, remain alive after progression; one is in CR following salvage radiotherapy. Six patients died due to nonrelapse causes, including two NHL patients who died while in CR. We conclude that HDMEL+AF+AHSCT has significant single-agent activity in relapsed or refractory NHL and HL. This experience may be used as a starting point for subsequent dose escalation of HDMEL (probably with AF) in established combination regimens.

Antiviral Responses following L-Leucyl-L-Leucine Methyl Esther (LLME)-Treated Lymphocyte Infusions: Graft-versus-Infection without Graft-versus-Host Disease

Although allogeneic hematopoietic progenitor cell transplant (HPCT) is curative therapy for many disorders, it is associated with significant morbidity and mortality, which can be related to graft-versus-host disease (GVHD) and the immunosuppressive measures required for its prevention and/or treatment. Whether the immunosuppression is pharmacologic or secondary to graft manipulation, the graft recipient is left at increased risk of the threatening opportunistic infection. Refractory viral diseases in the immunocompromised host have been treated by infusion of virus-specific lymphotyces and by unmanipulated donor lymphocyte infusion (DLI) therapy. L-leucyl-L-leucine methyl ester (LLME) is a compound that induces programmed cell death of natural killer (NK) cells, monocytes, granulocytes, most CD8(+) T cells, and a small fraction of CD4(+) T cells. We have undertaken a study of the use of LLME-treated DLI following T cell-depleted allogeneic HPCT, specifically to aid with immune reconstitution. In this ongoing clinical trial, we have demonstrated the rapid emergence of virus-specific responses following LLME DLI with minimal associated GVHD. This paper examines the pace of immune recovery and the rapid development of antiviral responses in 6 patients who developed viral infections during the time period immediately preceding or coincident with the administration of the LLME DLI.