Mary J. Laughlin

Umbilical cord blood (UCB) has been used successfully as a source of hematopoietic stem cells (HSCs) for allogeneic transplantation in children and adults in the treatment of hematologic diseases. ...

Book Review from The New England Journal of Medicine — Book Review

On activation, umbilical cord blood (UCB) CD4⁺ T cells demonstrate reduced expression of tumor necrosis factor- (TNF-) and interferon- (IFN-), whereas maintaining equivalent interleukin-2 (IL-2) levels, as compared with adult peripheral blood (PB) CD4⁺ T cells. Nuclear factor of activated T cells (NFAT1) protein, a transcription factor known to regulate the expression of IL-2, TNF- and IFN-, is reduced in resting and activated UCB CD4⁺ T cells. In contrast, expression of Broad-complex-Tramtrack-Bric-a-Brac and Cap'n'collar homology 1 bZip transcription factor 2 (BACH2) was shown by gene array analyses to be increased in UCB CD4⁺ T cells and was validated by qRT-PCR. Using chromatin immunoprecipitation, BACH2 was shown binding to the human IL-2 proximal promoter. Knockdown experiments of BACH2 by transient transfection of UCB CD4⁺ T cells with BACH2 siRNA resulted in significant reductions in stimulated IL-2 production. Decreased IL-2 gene transcription in UCB CD4⁺ T cells transfected with BACH2 siRNA was confirmed by a human IL-2 luciferase assay. In summary, BACH2 maintains IL-2 expression in UCB CD4⁺ T cells at levels equivalent to adult PB CD4⁺ T cells despite reduced NFAT1 protein expression. Thus, BACH2 expression is necessary to maintain IL-2 production when NFAT1 protein is reduced, potentially impacting UCB graft CD4⁺ T-cell allogeneic responses.

Summary: The dose of graft‐nucleated cells and CD34⁺ haematopoietic progenitor cells are predictors of allogeneic engraftment and survival in umbilical cord blood (UCB) recipients. In this single institution prospective phase II trial, flow cytometric analyses of CD34⁺ progenitor and lymphocyte populations in unmodified single unit human leucocyte antigen (HLA)‐disparate UCB grafts infused into 31 consecutive adults (median age 41 years, range 20–64) receiving myeloablative conditioning were compared with clinical outcomes. Median infused UCB graft‐nucleated cells and CD34⁺ dose was 2·2 × 10⁷/kg and 1·2 × 10⁵/kg respectively. Day to absolute neutrophil count ≥0·5 × 10⁹/l with full donor chimerism averaged 27 d (range 12–41). Univariate analyses demonstrated that UCB graft‐infused cell doses of CD34⁺ (P = 0·015), CD3⁺ (P = 0·024) and CD34⁺HLADR⁺CD38⁺ progenitors (P = 0·043) correlated with neutrophil engraftment. This same analysis did not demonstrate a correlation between CD34⁺ (P = 0·11), CD3⁺ (P = 0·28) or CD34⁺HLADR⁺CD38⁺ (P = 0·108) cell dose and event‐free survival (EFS). High‐resolution matching for HLA‐class II (DRB1) resulted in improved EFS (P = 0·02) and decreased risk for acute graft‐versus‐host disease (GVHD) (P = 0·004). Early mortality (prior to post‐transplant day +28) occurred in three patients, while 26 patients achieved myeloid engraftment. These results suggest that UCB graft matching at DRB1 is an important risk factor for acute GVHD and survival, while higher UCB graft cell doses of CD34⁺, committed CD34⁺ progenitors and CD3⁺ T cells favourably influence UCB allogeneic engraftment.

6647 Background: Bortezomib has been shown to be safe and effective single agent in the treatment of relapsed and refractory hematological malignancies. Fludarabine also is an active agent in treatment of indolent non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Bortezomib may potentiate fludarabine activity by inhibiting DNA repair and inducing apoptosis in Bcl-2 overexpressing cells. Methods: A phase I study combining bortezomib and fludarabine is being performed to determine the MTD/toxicities of this combination in patients with relapsed or refractory (progressive) indolent NHL or CLL. Cohorts of 3 patients received fludarabine 25mg/m² days 1–3 and escalating doses of bortezomib on days 1,4,8 and 11 in 3 week cycles. Results: Thus far 7 patients (indolent NHL=4, CLL=2, Mantle Cell NHL=1) are evaluated in 3 of 4 planned dose cohorts of bortezomib (0.7, 1.0 and 1.3 mg/m²). All patients were treated with 2–6 prior regimens (median 4). A total of 27 cycles of therapy has been given and the DLT has not been reached. All 7 patients experienced grade 3 lymphopenia, 1 had reversible grade 3 thrombocytopenia 1 had transient grade 3 neutropenia and 2 had grade 3 diarrhea unrelated to treatment. Grade 1 and 2 neurotoxicity was seen in 2 patients. One patient achieved CRu (follicular lymphoma), 1 PR (mantle Cell) and 4 had SD. One patient with CLL progressed after 1 cycle of therapy. There was no detectable change in levels of DNA-PKc, bcl-2, p27, p21, caspase 3, or ATM proteins in CLL cells of this patient on day 8 compared to day 1 at bortezomib dose of 1.0 mg/m². Conclusions: Combination of bortezomib and fludarabine is feasible and appears to be active in heavily pre-treated patients with indolent NHL. Dose escalation of bortezomib above 1.0 mg/m² continues to determine the MTD. No significant financial relationships to disclose.