A phase I trial of NK-92 cells for refractory hematological malignancies relapsing after autologous hematopoietic cell transplantation shows safety and evidence of efficacy.

BACKGROUND: Autologous NK cell therapy can treat a variety of malignancies, but is limited by patient-specific variations in potency and cell number expansion. In contrast, allogeneic NK cell lines can overcome many of these limitations. Cells from the permanent NK-92 line are constitutively activated, lack inhibitory receptors and appear to be safe based on two prior phase I trials. MATERIALS AND METHODS: We conducted a single-center, non-randomized, non-blinded, open-label, Phase I dose-escalation trial of irradiated NK-92 cells in adults with refractory hematological malignancies who relapsed after autologous hematopoietic cell transplantation (AHCT). The objectives were to determine safety, feasibility and evidence of activity. Patients were treated at one of three dose levels (1 × 109 cells/m2, 3 × 109 cells/m2 and 5 × 109 cells/m2), given on day 1, 3 and 5 for a planned total of six monthly cycles. RESULTS: Twelve patients with lymphoma or multiple myeloma who relapsed after AHCT for relapsed/refractory disease were enrolled in this trial. The treatment was well tolerated, with minor toxicities restricted to acute infusional events, including fever, chills, nausea and fatigue. Two patients achieved a complete response (Hodgkin lymphoma and multiple myeloma), two patients had minor responses and one had clinical improvement on the trial. CONCLUSIONS: Irradiated NK-92 cells can be administered at very high doses with minimal toxicity in patients with refractory blood cancers, who had relapsed after AHCT. We conclude that high dose NK-92 therapy is safe, shows some evidence of efficacy in patients with refractory blood cancers and warrants further clinical investigation.

A systematic review of transfusion-associated graft-versus-host disease.

Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare complication of blood transfusion. The clinicolaboratory features of TA-GVHD and the relative contributions of recipient and component factors remain poorly understood. We conducted a systematic review of TA-GVHD reports. The HLA relationship between donor and recipient was classified as D = 0 when no donor antigens were foreign to the recipient vs D ≥ 1 when ≥1 donor antigen disparity occurred. We identified 348 unique cases. Criteria for component irradiation were met in 48.9% of cases (34.5% immune-compromised, 14.4% related-donor), although nonirradiated components were transfused in the vast majority of these (97.6%). Components were typically whole blood and red cells. When reported, component storage duration was ≤10 days in 94%, and 23 (6.6%) were leukoreduced (10 bedside, 2 prestorage, and 11 unknown). Among 84 cases with HLA data available, the category of D = 0 was present in 60 patients (71%) at either HLA class I or II loci and was more common among recipients without traditional indications for component irradiation. These data challenge the historic emphasis on host immune defects in the pathogenesis of TA-GVHD. The dominant mechanism of TA-GVHD in both immunocompetent and compromised hosts is exposure to viable donor lymphocytes not recognized as foreign by, but able to respond against, the recipient.

Transfusion-related acute lung injury (TRALI) in graft by blood donor antibodies against host leukocytes.

It is unknown the extent to which transfusion-related acute lung injury (TRALI) contributes to primary graft dysfunction (PGD), the leading cause of death after lung transplantation. In this case of suspected transfusion-associated acute bilateral graft injury in a 61-year-old idiopathic pulmonary fibrosis patient, recipient sera from before and after transplantation/transfusion, as well as the sera of 22 of the 24 implicated blood donors, were individually screened by Luminex bead assay for the presence of human leukocyte antigen (HLA) antibodies, with recipient and lung donor HLA typing to explore for cognate relationships. A red-cell-unit donor-source anti-Cw6 antibody, cognate with the HLA type of the recipient, was identified. This is the second reported case of TRALI in the setting of lung transplantation, and the first to show an associated interaction between donor antibodies (in a low-plasma volume product) with recipient leukocytes (rather than graft antigens); therefore, it should be considered in the differential diagnosis of PGD.

Passenger lymphocyte syndrome with or without immune hemolytic anemia in all Rh-positive recipients of lungs from rhesus alloimmunized donors: three new cases and a review of the literature.

The passenger lymphocyte syndrome (PLS) is an unusual complication of solid organ transplantation, in which donor lymphocytes produce antibodies reactive with host red blood cell (RBC) antigens. Risks for PLS include highly lymphoid grafts, past sensitization of the donor against relevant RBC antigens, and donor lymphocyte escape of host immune clearance. For a 1-year period at our center, we observed an uncommonly high frequency of post-lung transplant Rhesus PLS, occurring once in every 31 cases. Passenger lymphocyte syndrome resulted from 2 alloimmunized cadaveric donors, in 3 of 3 D+, ABO-identical but HLA-unmatched recipients who initially had nonreactive RBC antibody screens. In case 1, the right lung of a group A, D-negative donor, with antibodies against D, C, and E antigens, was transplanted into a group A, R1R1 recipient. The recipient developed severe hemolytic anemia, direct antiglobulin test (DAT)-positive, on postoperative day (POD) 17. Anti-D and anti-C were identified on both the indirect antiglobulin test (IAT) and the RBC eluate. She required 10 U of RBCs in 40 days as well as plasmapheresis (POD 36-40). When transfusion dependence ceased, anti-D +/- C remained detectable on DAT and IAT for another 6.5 months. In case 2, the group A, R1r recipient of the same donor's left lung exhibited anti-D for the first time at posttransplant month 4 on both IAT and DAT. This activity persisted until a rejection episode 5 months later, without ever causing any evidence of hemolysis. In case 3, the group O, R1R1 recipient of both lungs of a group O, D-negative donor, with antibodies against D, C, and V antigens, developed a nonhemolytic DAT and IAT with anti-D +/- C at postoperative month 2, which remained positive at last follow-up (6 months posttransplant). In conclusion, this report suggests a high incidence of Rhesus antibody PLS after lung transplantation, with wide variations in the timing of antibody onset, persistence, and severity. A review of the phenomenon and its implications are discussed.