Modular Fluted Tapered Stems for Periprosthetic Femoral Fractures: Excellent Results in 171 Cases.

BACKGROUND: Modular fluted tapered (MFT) stems have advanced treatment of Vancouver B2 and B3 periprosthetic femoral fractures, but series to date have been limited with respect to cohort size and follow-up duration. The purpose of this study was to determine implant survivorship, radiographic results, complications, and clinical outcomes of Vancouver B2 and B3 periprosthetic femoral fractures treated with MFT stems in a large series of patients. METHODS: We identified 171 Vancouver B2 (109) and B3 (62) periprosthetic femoral fractures treated with an MFT stem between 2000 and 2018 using our institutional total joint registry. The mean age was 75 years, 50% were female, and the mean body mass index was 29 kg/m2. The median stem diameter was 18 mm and median stem length was 210 mm. The cumulative incidences of revision and reoperation with death as the competing risk were calculated, radiographs were reviewed, and clinical outcomes were evaluated using the Harris hip score (HHS). The mean follow-up was 5 years. RESULTS: The 10-year cumulative incidence of any revision was 10%. There were 17 revisions, of which only 3 were for the distal fluted portion of the MFT stem. Revision indications included periprosthetic joint infection (PJI) (n = 6) and dislocation (n = 11). The 10-year cumulative incidence of any reoperation was 15%. In addition to the above 17 revisions, there were 7 reoperations for superficial wound complications (n = 4), Vancouver B1 periprosthetic femoral fracture (n = 1), vascular occlusion (n = 1), and acetabular cartilage degeneration requiring an acetabular component (n = 1). Radiographically, there was 1 fracture nonunion. All unrevised MFT stems were radiographically well fixed. Subsidence of ≥5 mm occurred in 11%, but all implants were stable at the most recent follow-up. The mean HHS was 75 at 2 years (n = 71). CONCLUSIONS: In this large series of 171 Vancouver B2 and B3 periprosthetic femoral fractures treated with MFT stems, we found that such constructs were associated with a high rate of fracture healing and provided extremely reliable and durable implant fixation, with no revisions for aseptic loosening. Dislocation and PJI were the most common complications. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial.

Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.

Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal.

Preclinical studies have shown that persistent mixed chimerism is linked to acceptance of organ allografts without immunosuppressive (IS) drugs. Mixed chimerism refers to continued mixing of donor and recipient hematopoietic cells in recipient tissues after transplantation of donor cells. To determine whether persistent mixed chimerism and tolerance can be established in patients undergoing living donor kidney transplantation, we infused allograft recipients with donor T cells and hematopoietic progenitors after posttransplant lymphoid irradiation. In 24 of 29 fully human leukocyte antigen (HLA)-matched patients who had persistent mixed chimerism for at least 6 months, complete IS drug withdrawal was achieved without subsequent evidence of rejection for at least 2 years. In 10 of 22 HLA haplotype-matched patients with persistent mixed chimerism for at least 12 months, reduction of IS drugs to tacrolimus monotherapy was achieved. Withdrawal of tacrolimus during the second year resulted in loss of detectable chimerism and subsequent rejection episodes, unless tacrolimus therapy was reinstituted. Posttransplant immune reconstitution of naïve B cells and B cell precursors was more rapid than the reconstitution of naïve T cells and thymic T cell precursors. Robust chimerism was observed only among naïve T and B cells but not among memory T cells. No evidence of rejection was observed in all surveillance graft biopsies obtained from mixed chimeric patients withdrawn from IS drugs, and none developed graft-versus-host disease. In conclusion, persistent mixed chimerism established in fully HLA- or haplotype-matched patients allowed for complete or partial IS drug withdrawal without rejection.

Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients.

BACKGROUNDIn preclinical murine and early clinical studies of hematopoietic cell transplantation, engineering of donor grafts with defined ratios of CD4+CD25+FoxP3+ Tregs to conventional T cells (Tcons) results in the prevention of graft-versus-host disease and improved immune reconstitution. The use of highly purified primary graft Tregs for direct cell infusion has potential advantages over impure immunomagnetic selection or culture expansion, but has not been tested clinically. We performed a phase I study of the timed addition of CD34-selected hematopoietic stem cells and Tregs, followed by Tcons for the treatment of patients with high-risk hematological malignancies.METHODSWe present interim evaluation of a single-center open phase I/II study of administration of human leukocyte-matched Tregs and CD34-selected hematopoietic cells, followed by infusion of an equal ratio of Tcons in adult patients undergoing myeloablative hematopoietic stem cell transplantation (HCT) for high-risk or active hematological malignancies. Tregs were purified by immunomagnetic selection and high-speed cell sorting.RESULTSHere we report results for the first 12 patients who received Tregs of between 91% and 96% purity. Greater than grade II GVHD was noted in 2 patients in the first cohort of 5 patients, who received cryopreserved Tregs, but neither acute nor chronic GVHD was noted in the second cohort of 7 patients, who received fresh Tregs and single-agent GVHD prophylaxis. Patients in the second cohort appeared to have normal immune reconstitution compared with patients who underwent transplantation and did not develop GVHD.CONCLUSIONOur study shows that the use of highly purified fresh Tregs is clinically feasible and supports continued investigation of the strategy.TRIAL REGISTRATIONClinicalTrials.gov NCT01660607.FUNDINGNIH NHBLI R01 HL114591 and K08HL119590.

Infusion of donor-derived CD8+ memory T cells for relapse following allogeneic hematopoietic cell transplantation.

Murine models showed that CD8+CD44hi memory T (TM) cells could eradicate malignant cells without inducing graft-versus-host disease (GVHD). We evaluated the feasibility and safety of infusing freshly isolated and purified donor-derived phenotypic CD8+ TM cells into adults with disease relapse after allogeneic hematopoietic cell transplantation (HCT). Phenotypic CD8 TM cells were isolated after unmobilized donor apheresis using a tandem immunomagnetic selection strategy of CD45RA depletion followed by CD8+ enrichment. Fifteen patients received CD8+ TM cells at escalating doses (1 × 106, 5 × 106, or 10 × 106 cells per kg). Thirteen received cytoreduction before CD8+ TM cell infusion, and 9 had active disease at the time of infusion. Mean yield and purity of the CD8+ TM infusion were 38.1% and 92.8%, respectively; >90% had CD8+ T effector memory phenotype, cytokine expression, and secretion profile. No adverse infusional events or dose-limiting toxicities occurred; GVHD developed in 1 patient (grade 2 liver). Ten patients (67%) maintained or achieved response (7 complete response, 1 partial response, 2 stable disease) for at least 3 months after infusion; 4 of the responders had active disease at the time of infusion. With a median follow-up from infusion of 328 days (range, 118-1328 days), median event-free survival and overall survival were 4.9 months (95% confidence interval [CI], 1-19.3 months) and 19.6 months (95% CI, 5.6 months to not reached), respectively. Collection and enrichment of phenotypic CD8+ TM cells is feasible, well tolerated, and associated with a low incidence of GVHD when administered as a manipulated infusion of donor lymphocytes in patients who have relapsed after HCT. This trial was registered at www.clinicaltrials.gov as #NCT01523223.

Adoptive immunotherapy with cytokine-induced killer cells for patients with relapsed hematologic malignancies after allogeneic hematopoietic cell transplantation.

Donor leukocyte infusions induce remissions in some patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (HCT); however, graft-versus-host disease (GVHD) remains the major complication of this strategy. Cytokine-induced killer (CIK) cells are a unique population of cytotoxic T lymphocytes that express the CD3(+)CD56(+) phenotype and show marked up-regulation of the natural killer cell receptor NKG2D (CD314). CIK cells are non-major histocompatibility complex-restricted and NKG2D-dependent in target recognition and cytotoxicity. We explored the feasibility of ex vivo expansion of allogeneic CIK cells in patients with relapsed hematologic malignancies after allogeneic HCT. Eighteen patients (median age, 53 years; range, 20-69 years) received CIK cell infusions at escalating doses of 1 × 10(7) CD3(+) cells/kg (n = 4), 5 × 10(7) CD3(+) cells/kg (n = 6), and 1 × 10(8) CD3(+) cells/kg (n = 8). The median expansion of CD3(+) cells was 12-fold (range, 4- to 91-fold). CD3(+)CD56(+) cells represented a median of 11% (range, 4%-44%) of the harvested cells, with a median 31-fold (range, 7- to 515-fold) expansion. Median CD3(+)CD314(+) cell expression was 53% (range, 32%-78%) of harvested cells. Significant cytotoxicity was demonstrated in vitro against a panel of human tumor cell lines. Acute GVHD grade I-II was seen in 2 patients, and 1 patient had limited chronic GVHD. After a median follow-up of 20 months (range, 1-69 months) from CIK infusion, the median overall survival was 28 months, and the median event-free survival was 4 months. All deaths were due to relapsed disease; however, 5 patients had longer remissions after infusion of CIK cells than from allogeneic HCT to relapse. Our findings indicate that this form of adoptive immunotherapy is well tolerated and induces a low incidence of GVHD, supporting further investigation as an upfront modality to enhance graft-versus-tumor responses in high-risk patient populations.

CD34, CD4, and CD8 cell doses do not influence engraftment, graft-versus-host disease, or survival following myeloablative human leukocyte antigen-identical peripheral blood allografting for hematologic malignancies.

OBJECTIVES: Optimal granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cell (G-PBMC) graft compositions for myeloablative allogeneic hematopoietic cell transplantation (AHCT) have not been identified. G-PBMC cell contents were analyzed for influence on outcomes. PATIENTS AND METHODS: Human leukocyte antigen(HLA)-identical related donor AHCT was used to treat 101 patients with hematologic malignancies at a single institution between 1995 and 2002. CD34+, CD3+, CD4+, and CD8+ cell doses were enumerated by flow cytometry and evaluated by univariate analysis. RESULTS: Categorized by the median of cell doses infused, no G-PBMC cell dose significantly correlated with neutrophil and platelet engraftment. Incidence of grade II to IV acute graft-versus-host disease (GVHD) was 24.6% (95% confidence interval [CI]: 15.9-33.3) and was not significantly influenced by evaluated G-PBMC cell doses. With a median follow-up time of 18 months for surviving patients, estimates for extensive chronic GVHD was 43.8% (95% CI: 31.4-56.2), for freedom from progression was 69.5% (95% CI: 58.1-80.9), and for overall survival was 46.9% (95% CI: 35.5-58.3). CD34+, CD3+, CD4+, and CD8+ cell doses were not significantly predictive of extensive chronic GVHD, freedom from progression or overall survival. Additionally, comparing patients receiving the upper versus lower 33rd percentiles of CD34+ cell dose, associations with extensive chronic GVHD remained insignificant (p=0.21; relative risk (RR)=1.7; 95% CI: 0.7-3.9). CONCLUSIONS: G-PBMC graft content does not influence outcomes after myeloablative AHCT. In particular, no significant association between extensive chronic GVHD was identified with any G-PBMC cell dose, including CD34.

Engraftment and survival following reduced-intensity allogeneic peripheral blood hematopoietic cell transplantation is affected by CD8+ T-cell dose.

The influence of graft composition on clinical outcomes after reduced-intensity conditioning is not well-characterized. In this report we prospectively enumerated CD34+, CD3+, CD4+, and CD8+ cell doses in granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) allografts in 63 patients who received transplants following non-myeloablative conditioning with total body irradiation 200 cGy plus fludarabine as treatment for malignant diseases. Donors were HLA-identical siblings (n = 38) or HLA-matched unrelated individuals (n = 25). By univariate analyses G-PBMC CD8+ T-cell dose in at least the 50th percentile favorably correlated with full donor blood T-cell chimerism (P = .03), freedom from progression (P = .001), and overall survival (P = .01). No G-PBMC cell dose influenced grade II to IV acute or extensive chronic graft-versus-host disease. In multivariate analysis only G-PBMC CD8+ T-cell dose (P = .003; RR = 0.2, 95% CI = 0.1-0.6) was associated with improved freedom from progression. Infusion of low G-PBMC CD8+ T-cell dose for reduced-intensity allografting may adversely affect T-cell engraftment and survival outcome.