Incidence of Infectious Complications in MDS/AML Patients Treated with Azacitidine By the Italian Cooperative Groups Gruppo Romano MDS (GROM) and Basilicata MDS Registry
Authors: Voso Maria Teresa , Niscola Pasquale , Piciocchi Alfonso , Pagano Livio , Maurillo Luca , Musto Pellegrino , Fianchi Luana , Mansueto Giovanna , Aloe-Spiriti Antonietta , Buccisano Francesco , Venditti Adriano , Tendas Andrea , Mancini Stefano , Piccioni Anna Lina , Andriani Alessandro , Latagliata Roberto , Alimena Giuliana , Filardi Nunzio , Fragasso Alberto , Tafuri Agostino , Fenu Susanna , Breccia Massimo 
Published: October 2019

Abstract
Azacitidine (AZA) is the standard of care for higher-risk myelodysplastic syndromes (MDS). Cytopenias are a major problem during the first treatment cycles due to MDS itself and to the mechanism of action of the drug, which includes not only demethylation, but also cytotoxicity and apoptosis.
We evaluated the incidence of infectious complication during AZA treatment in 200 “real life” patients, collected retrospectively by the italian cooperative groups Gruppo Romano MDS (GROM) and Basilicata MDS Registry. Patients gave informed consent and the study was approved by the Ethycal Committes of partecipating Centers. Patient started AZA between 3/2006 and 3/2014. Median age at treatment start was 71 years (range 33-93 yrs, 66 females, 134 males). There were 182 MDS (up to 20% BM-Blasts) and 18 AML (median BM-blasts 23%, range 21-60% BM-blasts). In MDS, IPSS stratification (n=178) was: low: 4%, Int-1: 19%, Int-2: 60%, high 17%, and according to R-IPSS (n=123 pts): low: 4%, intermediate: 20%, high: 51%, very-high: 20%. MDS-specific comorbidity index (MDS-CI) was available for 154 patients: 50 patients were classified as low-risk (0), 85 as intermediate (1-2), and 19 as high risk (>2). Azacitidine was started at a median of 1.4 months from initial diagnosis. One-hundred-sixty-six patients received AZA at the standard dose of 75 mg/sqm (7 days continuously: 22%, 5-2-2 days: 64%, 6-1-1: 4%) while 34 patients received AZA at 50 mg/sqm for 5- 7 days.
Response, according to IWG 2006 criteria, was evaluable in 188 patients: 27 obtained complete remission (CR, 14%), marrow CR was achieved in 6 (3%), partial remission (PR) in 30 (16%), hematological improvement (HI) in 40 (21%), disease was reported stable (SD) in 54 (29%), whereas 31 patients presented progressive disease (16%). A median of 10 (range 1-62) cycles of AZA were delivered. Probability of response was independent from age, IPSS, IPSS-R, MDS-CI, and was associated to a shorter time from diagnosis to therapy initiation (p=0.04) and to the 75 mg/sqm through 7 days vs 50 mg/sqm through 5 -7 days schedule (60 vs 30% CR/PR/HI, p=0.007). With a median follow-up of 14.8 months (range 0-100 months), 57 patients are alive, resulting into a median overall survival of 17.2 months. IPSS and MDS-CI did not predict survival, while grouping according to IPSS-R was associated to a significantly different survival probability (p=0.0007).
Across delivery of a total of 1547 AZA cycles, 213 (13%) febrile events were recorded. Fever of unknown origin was diagnosed in 20 patients (10%). Of 193 clinically documented events, a positive microbiologic test was available in 49 cases (25%, 44 for bacteria, 5 for viruses). A single episode of infection was recorded in 124 patients (62%) at a median of 3.8 months from therapy initiation (0-53 months), 53 (26.5%) patients suffered from a second infectious event and 28 (14%) patients from a third one (at 5.6 and 8.3 months from AZA start, respectively). Infections were the attributable cause of death in 30 patients (15%, 3 in CR, 17 with progressive disease and 10 SD). Most frequent infection sites were lungs (45%), cutis (9%), mouth (9%), bowel or peri-anal region (7%). The risk of infectious complications was lower in IPSS low-risk (p=0.05) or IPSS-R low/int MDS (p=0.01), and in patients with MDS-CI 0-2 (p=0.0001).
Our data indicate that treatment with AZA is associated with a relatively high probability to develop infectious complications, especially pneumonia, which is however rarely the cause of death. The risk to develop infections is the highest during the first courses of AZA delivery and correlates to baseline patients’ characteristics, including disease stage and comorbidities. Once the infectious episode has occurred, the outcome depends on the disease status.

Disclosures
Voso: Celgene: Consultancy. Venditti:celgene: Consultancy. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy.