The update yielded a total of 3,590 person-years of follow-up, versus 2,043 in the prior report. Follow-up was censored in 19 patients who received a bone marrow transplant. There were 849 person-years among 176 patients treated for 10 or more years; versus just 67 person-years among 60 patients previously. In all, there were 61 MDS/AML events and 29 sepsis deaths, versus prior totals of 44 and 19, respectively. After including up-to-date follow-up, the estimated annual hazard of sepsis death remained qualitatively stable, at 0.81%/year (95% CI: 0.56 – 1.16%/year). Similarly, during the first five years after the start of G-CSF therapy, the updated estimate of the hazard curve for MDS/AML showed the same increasing trend as the previous estimate (). However, in contrast to the prior estimate that showed an increasing trend after year 5 (with a large margin for error), the updated hazard curve attained a plateau, with confidence intervals for the new hazard curve considerably narrower than corresponding intervals in our earlier report. After 10 years on G-CSF, the estimated hazard of MDS/AML was 2.3%/year (95% CI: 1.7 – 2.9%/year).
Hazard rates and cumulative incidence of MDS/AML and sepsis death in patients with SCN
Whereas the long-term hazard of MDS/AML now appears significantly lower than first suggested, substantial numbers of sepsis deaths and cases of MDS/AML accumulated over time. After 15 years on G-CSF, the cumulative incidence was 10% (95% CI: 6 – 14%) for sepsis death and 22% (95% CI: 17 – 28%) for MDS/AML ). In the initial dataset, the corresponding estimates of cumulative incidence attained similar values earlier, 8% and 21% at 10 years, respectively.
With additional follow-up, the association of G-CSF dose at 6 months with the relative hazard of MDS/AML became more strongly statistically significant (P = 0.003 versus P = 0.024; the hazard of MDS/AML increased by 1.24-fold [95% CI: 1.08-1.43-fold] per doubling of the G-CSF dose). In contrast, the association of G-CSF dose at 6 months with the relative hazard of sepsis death was slightly attenuated (P = 0.053 versus P = 0.039; the hazard of sepsis death increased by 1.25-fold [95% CI: 1.00 – 1.56-fold] per doubling).
As in the previous analysis, the subset of patients who failed to achieve a mean ANC count at or above the median for the cohort (2.188×109/l) despite doses of G-CSF at or above the median (8 μg/kg/day), were at elevated risk of both sepsis death and MDS/AML, compared with patients who achieved a good response at a lower dose (i.e., median ANC count above 2.188 ×109/l on G-CSF below 8 μg/kg/day). In the low-risk group, the cumulative incidence after 15 years on G-CSF was 5% (95% CI: 0 – 12%) for sepsis death and 15% (95% CI: 4 – 25%) for MDS/AML (), versus 18% (95% CI: 7 – 28%) and 34% (95% CI: 21 – 47%), respectively, in the high-risk group ().
Cumulative incidence of MDS/AML and sepsis death in subgroups of SCN patients
This analysis incorporates extended follow-up of the largest existing cohort of patients with SCN, which has allowed us to estimate the long-term risks with greater precision. Overall, comparisons of the new results (2009) with the old (2001) are very consistent. However, there is one important exception: in all patients combined, the hazard of MDS/AML now appears to be around 2.3%/year after 10 years on G-CSF, substantially below the range of 4 – 12%/year suggested by prior unstable data.
This is good news for patients and their physicians. Also, the reduced hazard estimate for MDS/AML helps resolve an etiological conundrum. From a molecular perspective, it was not entirely clear why susceptibility to leukaemia appeared higher in SCN than in other high-risk inherited bone marrow failure syndromes, including the DNA repair disorder of Fanconi anemia (FA) (Rosenberg, et al 2003
) or the telomere maintenance syndrome of dyskeratosis congenita (DC) (Alter, et al 2009
). Indeed, the high incidence of leukaemic transformation in SCN has raised concerns that G-CSF may promote malignant clones (Donadieu, et al 2005
). In light of these new data, it now appears that the rate of MDS/AML in SCN is qualitatively quite similar to the rate of AML in both FA and DC. Furthermore, a plateau is now seen in SCN, similar to that for FA.
The positive news in this report must be put in perspective. Although the hazard curve for MDS/AML in SCN now appears to plateau, the cumulative incidence still attains high levels, albeit more slowly. Hence, it is imperative that all patients continue to be closely monitored for leukemic transformation. Furthermore, the risks and benefits of early haematopoietic stem cell transplantation should be evaluated for the subset of patients who respond poorly to a high dose of G-CSF.