Janet Hayden

IL-17-producing CD4(+) T cells, pro-inflammatory cytokines and apoptosis are increased in low risk myelodysplastic syndrome.

Immunological responses are increasingly recognised as being important in the initiation and progression of myelodysplastic syndrome (MDS). Indeed, autoimmune diseases commonly occur in association with MDS, particularly in subtypes with a low risk of leukaemic transformation. This study showed for the first time that the numbers of CD3+ CD4+ IL‐17 producing T cells (Th17) were markedly increased in low risk MDS compared with high risk MDS (P < 0·01). An inverse relationship between the numbers of Th17 cells and naturally occurring CD4+CD25high FoxP3+ regulatory T cells (Tregs) were also described. The Th17:Tregs ratio was significantly higher in low risk disease (P < 0·005) compared with high risk MDS and was correlated with increased bone marrow (BM) apoptosis (P < 0·01). Tregs from MDS patients suppressed interferon‐γ (IFN‐γ) secretion by effector CD4+ T cells but had no effect on interleukin (IL)‐17 production. In addition, the serum levels of IL‐7, IL‐12, RANTES and IFN‐γ are significantly elevated in low risk MDS, while inhibitory factors, such as IL‐10 and soluble IL‐2 receptor, are significantly higher in high risk disease. The ‘unfavourable’ Th17:Tregs ratio in low risk MDS may explain the higher risk of autoimmunity and the improved response to immune suppression in patients with low risk MDS compared to those with high risk disease.

Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia

We evaluated a novel alemtuzumab-based conditioning regimen in HSCT for acquired severe aplastic anemia (SAA). In a multicenter retrospective study, 50 patients received transplants from matched sibling donors (MSD; n = 21) and unrelated donors (UD; n = 29), using fludarabine 30 mg/m² for 4 days, cyclophosphamide 300 mg/m² for 4 days, and alemtuzumab median total dose of 60 mg (range:40-100 mg). Median age was 35 years (range 8-62). Overall survival at 2 years was 95% ± 5% for MSD and 83% for UD HSCT (p 0.34). Cumulative incidence of graft failure was 9.5% for MSD and 14.5% for UD HSCT. Full-donor chimerism (FDC) in unfractionated peripheral blood was 42%; no patient achieved CD3 FDC. Acute GVHD was observed in only 13.5% patients (all grade I-II) and only 2 patients (4%) developed chronic GVHD. A low incidence of viral infections was seen. Factors influencing overall survival were HSCT comorbidity 2-year index (92% with score 0-1 vs 42% with score ≥ 2, P < .001) and age (92% for age < 50 years vs 71% ≥ 50 years, P < .001). Our data suggest that the use of an alemtuzumab-based HSCT regimen for SAA results in durable engraftment with a low incidence of chronic GVHD.

Impact of pre-transplant serum ferritin on outcomes of patients with myelodysplastic syndromes or secondary acute myeloid leukaemia receiving reduced intensity conditioning allogeneic haematopoietic stem cell transplantation

We report on a retrospective analysis examining the influence of pre-transplant serum ferritin on transplant outcomes of 99 MDS patients receiving reduced intensity conditioning (RIC) HSCT. The median pre-transplant ferritin value was 1992 ng/ml (range: 6-9580 ng/ml). No patients received iron chelation therapy preceding transplantation. On univariate analysis, there was a strong correlation between a higher pre-transplant serum ferritin (>1500 ng/ml) and a significantly inferior 3-year OS (64.6+/-7.5% vs 39.6+/-7.3%, p=0.01). However, pre-transplant serum ferritin did not influence 3-year TRM (20.2+/-7% vs 27.4+/-7%, p=0.24). There was no difference in infection-related mortality, and incidence of acute or chronic GvHD between cohorts. On multivariate analysis, a raised serum ferritin (HR: 2.00, 95% CI: 0.97-3.57, p=0.03), and the presence of >5% bone marrow blasts at time of transplantation (HR: 2.14, 95% CI: 0.84-4.58, p=0.06) were independent predictors of an inferior overall survival. However, pre-transplant serum ferritin was not a significant predictor of disease-free survival, relapse or TRM. When compared with myeloablative regimens, RIC regimens may attenuate the impact of iron overload related end-organ toxicity. Prospective studies incorporating alternative biomarkers of iron metabolism alongside serum ferritin levels are needed to improve our understanding of the significance of iron overload in MDS patients undergoing allogeneic transplantation.

Successful pregnancies involving men with chronic myeloid leukaemia on imatinib therapy

Imatinib mesylate (STI 571, Glivec, Gleevec; Novartis, Basel, Switzerland) is used for the first line management of chronic myeloid leukaemia in chronic and accelerated phase (Druker et al, 2006). Although developed to inhibit selectively the bcrabl tyrosine kinase, Imatinib has been subsequently discovered to inhibit potently other tyrosine kinases, such as c-abl, c-kit and platelet-derived growth factor receptor (PDGFR). Murine studies have demonstrated imatinib-induced teratogenesis and its effects on spermatogenesis appear to be dose-related (http:// www.pharma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf). Male rats exposed to 75% of the maximum human equivalent dose of 800 mg/d for about 70 d prior to mating had lower epididymal and testicular weight along with reduction in the number of motile sperm. Summary product characteristics recommend strict avoidance in pregnant women. Although there are reports of successful pregnancies on imatinib therapy, there have also been reports of spontaneous abortion and meningocoele in the literature, highlighting potential risks of conception whilst undergoing imatinib therapy (Ault et al, 2006). To date, there are limited data available on the outcome of pregnancies that occur while the male partner is receiving imatinib. We report here on five healthy pregnancies conceived from four male patients on long-term imatinib therapy. In our four patients, median duration of imatinib exposure prior to conception was 18 months (range: 4–48 months) and their median age was 45 years (range: 41–46 years). Three patients were on an imatinib dose of 600 mg/d or greater at the time of conception. Cumulative imatinib dose prior to conception ranged from 48 to 852 g (median 216 g). All the patients were compliant and tolerated imatinib therapy, achieving a significant response (Table I). Sperm counts and levels of androgens were not performed, as patients had no symptoms suggestive of impotence. Partners of all four men had an uneventful full-term delivery by normal vaginal delivery except for one, which was by caesarean section. Birth weights and lengths were between 25th and 75th centiles, and duration of stay in hospital was comparable with that of normal deliveries. Ault et al (2006) reported on the outcome of pregnancies involving eight men (median age 35 years; range: 26–38 years) at a median dose of imatinib 700 mg/d and exposure period of 20 months. Of the eight reported pregnancies, there was one case of spontaneous abortion and of the seven successful pregnancies there was one baby born with gut malrotation needing surgical intervention (Ault et al, 2006). Hensley and Ford (2003) reported four normal pregnancies: two therapeutic abortions, one spontaneous abortion and one death in utero at 13 weeks in eight of 13 completed pregnancies involving male patients on imatinib therapeutic trials. Oligospermia has been reported in one patient on imatinib at a dose of 800 mg/d for at least 6 months for chronic eosinophilic leukaemia (Seshadri et al, 2006). Gynaecomastia has also been noted in seven patients, median age 60 years (39–84 years) on imatinib therapy at a dose of 600–800 mg/d (Gambacorti-Passerini et al, 2003). In these patients, testosterone levels were low and progesterone levels were high and median onset of gynaecomastia was at 12 (5–13) months of therapy. Inhibition of C-kit and PDGFR expression in testicular tissue by Imatinib has been speculated to be causative in testosterone reduction. We report on five uneventful pregnancies in partners of patients who were on prolonged high-dose imatinib therapy