Kenneth F. Bradstock

Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m² daily for 5 days, etoposide 75 mg/m² daily for 5 days, and idarubicin 9 mg/m² daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation (P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

Summary: Gastrointestinal toxicity, including oral mucositis, is a frequent complication of intensive combination chemotherapy for acute myeloid leukaemia (AML) and contributes substantially to treatment‐related mortality. We conducted a placebo‐controlled randomized trial to evaluate the efficacy of palifermin (keratinocyte growth factor), given at 60 μg/kg per daily IV for 3 d before and after chemotherapy, for mucosal protection in adult patients with previously untreated AML receiving induction therapy with idarubicin, high‐dose cytarabine and etoposide. Among 155 randomized patients, there was no statistically significant difference in the rate of grade 3 and 4 oral mucositis (primary study endpoint) between the two treatment arms (three in palifermin arm (4%), 8 in placebo arm (10%; P = 0·21); however, when considering the severity of oral mucositis (World Health Organization grade 0–4), there was evidence of reduced rates of higher grades of oral mucositis in the palifermin arm (P = 0·0007, test for trend). There was a statistically significantly lower rate of grades 3 and 4 gastrointestinal adverse events in the palifermin arm (21% vs. 44% in placebo arm; P = 0·003), mainly due to a reduction in severe diarrhoea (8% palifermin, 26% placebo; P = 0·01). Palifermin has activity as a mucosal protectant in AML patients receiving intensive chemotherapy. This trial is registered at ACTRN012605000095662.

Background Dendritic cells (DC) are important in the development of acute graft-versus-host disease (GVHD) after allogeneic hemopoietic cell transplantation (alloHCT). The trafficking of immature DC from blood to GVHD target organs is likely to be regulated by chemokine receptors. Methods We performed flow cytometry to document the expression of chemokine receptors on circulating DC and correlated the findings after alloHCT with occurrence of acute GVHD. Results In normal individuals, plasmacytoid DC (pDC) expressed high levels of CCR5, whereas the major CD16⁺ myeloid DC subpopulation lacked CCR5. However, its expression on CD16⁺ cells was induced by culture in allogeneic mixed lymphocyte reaction supernatant, an effect largely mediated by interferon-γ. CCR5 was expressed on a significant proportion of CD16⁺ DC in 42 alloHCT patients, whereas it was down-regulated on pDC. The maximum percentage of CCR5⁺CD16⁺ DC, at any time after transplantation, correlated with acute GVHD, whereas the minimum CCR5⁺ on pDC showed a similar correlation. Before developing signs of GVHD, the maximum percentage CCR5⁺CD16⁺ DC was higher in patients with GVHD grades II to IV than in GVHD grades 0 and I, whereas the minimum percentage CCR5 on pDC was lower in GVHD grades II to IV than in GVHD grades 0 and I. CCR5 levels more than 20.5% on CD16⁺ myeloid DC and less than 22.6% on CD123⁺ pDC correlated with subsequent GVHD grades II to IV with high sensitivities and specificities. Conclusions These observations may reflect DC activation and altered homing during the alloimmune response and could allow early diagnosis and therapeutic intervention before the clinical diagnosis of GVHD.

Aims: To demonstrate safety and efficacy of haploidentical bone marrow transplantation with non‐myeloablative conditioning and high‐dose post‐transplant cyclophosphamide in adult patients with leukaemia or lymphoma.Background: Human leukocyte antigen haploidentical bone marrow transplantation is a treatment option in patients with haematological malignancies who have no available human leukocyte antigen‐matched donor but is limited by conditioning regimen toxicity, graft failure, relapse and graft‐versus‐host disease (GvHD).Methods: Twelve patients, median age of 51 years, underwent transplantation with T cell replete bone marrow from a haplotype‐matched relative. The conditioning regimen consisted of cyclophosphamide, fludarabine and low‐dose total body irradiation. Post‐transplant immunosuppression consisted of a single dose of cyclophosphamide 50 mg/kg on day 3, followed by oral tacrolimus and mycophenolate mofetil. Outcomes reported are overall survival, engraftment and chimerism, toxicity, and clinical outcome.Results: All patients had neutrophil recovery (median 14.5 days), and 11 of 12 had platelet engraftment (median 17 days). Two patients had autologous reconstitution. Seven of nine assessable patients had complete donor chimerism. Four patients had grades II‐III GvHD, and none had grade IV GvHD. Four patients developed limited stage chronic GvHD. Five patients with acute myeloid leukaemia relapsed. Two patients died of nonrelapse causes, both from other malignancies, and five patients remain alive and relapse free. Median overall survival was 324 days (range 88–1163).Conclusion: This regimen is feasible and well tolerated in older patients with high‐risk leukaemia or lymphoma, with minimal short‐term toxicity and low rates of GvHD. The proportion of disease‐free survivors indicates a graft‐versus‐malignancy effect is present in survivors.