Prognostic Factors of Severe Infections, and Effect of Primary Anti-Infectious Prophylaxis in MDS Patients Treated with Azacitidine (AZA). A Single Center Study On 144 Patients

Hypomethylating agents, especially AZA, have become the reference treatment of higher risk MDS. Myelosuppression, although less important than with chemotherapy, is however notable especially during the first cycles of AZA, leading to potentially life threatening infections(Santini, Eur J Haematol 2010), and often to delay or discontinuation of treatment. Prognostic factors of severe infections in MDS patients (pts) receiving AZA have however not systematically been evaluated, and whether infection prophylaxis would be useful in this situation is unknown.

Between January 2005 and November 2011, we treated at our institution 155 consecutive MDS pts, including FAB RAEB-T/WHO AML 20–30% blasts with AZA (75 mg/m2/d ×7 d every 4 weeks). Between March 2008 and November 2011 most of them (n=90) received primary prophylaxis (PRO+) with levofloxacin 500 mg/d and Posaconazole 200 mg tid started at onset of the first cycle, and planned for the first 6 cycles. G-CSF was not used. We analyzed the number of hospitalizations for sepsis requiring IV antibiotics during the first 4 cycles of AZA, the severity of those infections (admission in ICU, death) and factors influencing the severity and outcome of those episodes in this PRO+cohort. The PRO+ cohort was compared with MDS treated with AZA between January 2005 and March 2008 at our center, who received no antibiotic prophylaxis(PRO-; n=54). 11 pts who received secondary prophylaxis were excluded from the present analysis.

The patient population (PRO+ and PRO-) included 144 pts (68% males). IPSS was high, int 2, int 1 in 36%, 46% and 18% of the pts, respectively. The median number of AZA cycles administered was 6 (range 1–41) and, according to IWG2006 criteria, 26 (18%), 7 (5%), 13 (9%) and 15 (10%) pts achieved CR, PR, mCR and stable disease (SD) with HI, respectively leading to an overall response rate of 42%. With a median follow-up of 28 months, median OS was 18 months.

Overall, 49 pts (34%) were hospitalized for sepsis during the first 4 cycles of AZA, including 7 (5%) in ICU, and 21 (14.5%) died from sepsis. The only prognostic factor of fatal infections was baseline ANC (median 0.7 G/L in pts with fatal infection vs 1.9 G/L in other pts, p= 0.0348), while age, sex, IPSS, cytogenetics and bone marrow blast % had no influence. Admission in ICU tended to be more frequent in males (all ICU pts were males, p=0.09), and was more frequent in pts with low baseline ANC (0.2 vs 1.7 G/L,p=0.04) and younger pts (median 67 vs 70, p=0.032), this last parameter being probably a bias related to some age limitation for admission in ICU. Other parameters (IPSS, marrow blasts, karyotype) had no significantly prognostic value for ICU admission.

90 pts received antiprophylaxis with Levofloxacin and Posaconazole (PRO+) and 54 did not (PRO-). Baseline characteristics (including age, sex, marrow blast %,Karyotype according to IPSS or IPSS-R, and IPSS) were similar between PRO+ and PRO- patients, except that baseline ANC<1G/l was more frequent in PRO + pts (47% vs 31% in PRO- pts, p=0.04). The ORR was 49% in PRO+ and 43% in PRO- pts (p=0.32). In spite of lower ANC in pts who died from infection, and lower baseline ANC in PRO+ pts, the proportion of hospitalization for sepsis(29% vs 39%, p= 0.33), deaths due to infection (11.5% v 16.8%, p=0.275) and admission in ICU (9% vs 4%, p= 0.251) were similar in PRO+ and PRO- pts. Moreover, among pts with baseline ANC<1G/L, there was a trend for a lower incidence of deaths due to infection in PRO+ than in PRO- (11% v 30%, p=0.076). PRO+ pts had a higher probability of receiving >= 6 cycles of AZA (76 vs 61% in PRO-pts, p=0.04). Median OS was 22.6 months in PRO+ and 15.7 months in PRO- pts (p=0.17).

Baseline ANC was the only factor significantly influencing the incidence of hospitalization in ICU for infection and the risk of fatal infection in MDS treated with AZA. In this comparison, primary anti infectious prophylaxis (PRO+) was not associated with a clear reduction in the incidence of infections requiring hospitalization and of fatal infections. However, the fact that ANC below 1G/L was associated with more infectious deaths, that ANC was lower in PRO+ pts and that patients with ANC <1G/L tended to have fewer infectious deaths when they received PRO may suggest some protective effect of antibiotic prophylaxis. This effect, which may have contributed to the fact that more PRO+ pts could receive>= 6 cycles of AZA, will have to be confirmed in prospective studies.

Fenaux:Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Novartis: Honoraria, Research Funding.