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Background: Comorbidities and body mass index (BMI) are significantly associated with outcome in patients (pts) who receive continue treatment with tyrosine kinase inhibitors (TKIs), such as in Ph+ leukemias. Ruxolitinib (RUX) is the first JAK1/2 inhibitor that may induce spleen/symptom responses and improve quality of life in pts with myelofibrosis (MF). Up-to-date, no data are available on the impact of comorbidities and BMI on pts treated with RUX. Aims: To evaluate the impact of comorbidities and BMI on responses, overall survival (OS) and maintenance of RUX dose in a large cohort of pts. Methods: Data were extracted from an electronic database that included retrospective data on pts treated before January 2015 in 16 Italian Hematology centers. Response to RUX was evaluated according to IWG-MRT criteria. BMI was calculated at the time of start of RUX and classified according to WHO criteria. Comorbidities were recorded at the time of start of RUX and classified according to the Charlson Comorbidity Index (CCI). Overall survival (OS) was calculated from the date of RUX start to the time of death or to last follow-up, whichever came first. Results: Between June 2011 and Apr 2016, 289 pts with PMF (52.6%), or PET-MF (17%) or PPV-MF (30.4%) were treated with RUX in participating Centers. At RUX start, median age was 68.4 years (range 39-89) with a male prevalence (56.4%); International Prognostic Score System (IPSS) was intermediate (intm)-1 (15.6%), intm-2 (45.3%), high (39.1%). Transfusion dependence and spleen enlargement were present in 26.6% and 96.9% of pts, respectively (69.6% with spleen≥ 10 cm). Median total symptom score (TSS) was 20 (range 0-70). JAK2V617F was present in 80.3% of 234 evaluable pts. Median follow-up from MF diagnosis was 3.8 yr (range 0.3-29.6) and median RUX exposure was 20 months (3-56.2). Overall, comorbidities were evaluable in 275 pts. CCI stratification showed the absence of comorbidities in 100 pts (36.4%), one comorbidity in 63 pts (22.9%) and two or more in 112 pts (40.7%). Compared to pts with CCI 2y from MF diagnosis was lower if CCI≥2 (33.9% vs 54%, p=0.001). Higher CCI did not correlate with lower spleen response (achieved by 45.2% vs 34.7%, p=0.09), TSS response (90.1% vs 83.2%, p=0.11), and higher incidence of RUX-induced anemia (Hb OS was significantly higher in pts with CCI BMI was evaluable in 269 pts: 169 pts (62.8%) were classified as under-weight/normal for a BMI Summary: In MF pts treated with RUX, BMI and comorbidities did not influence the achievement of spleen/symptom responses, maintenance of RUX dose or onset of drug-related anemia. Although CCI stratification correlated with survival, as in Ph+ leukemias treated with TKIs, the achievement of a spleen response was able to counterbalance the negative prognostic effect of a higher CCI. Consequently, higher BMI and CCI should not be regarded as contraindication to RUX therapy. Figure Figure. Disclosures Breccia: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Bonifacio:Ariad Pharmaceuticals: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding. Cimino:Bristol-Mayer: Honoraria; Celgene: Honoraria. Latagliata:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Cavo:Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria.

The polymorphisms on chromosome 9p21 play a role in the risk for cardiovascular events in chronic myeloid leukemia patients? Chronic myeloid leukemia (CML) is an onco-haematological disease due to the aberrant expression of an onco-protein with constitutive tyrosine kinase activity. The average age of onset is 55-60 years. The treatment with tyrosine kinase inhibitors (TKIs) drastically changed the outcome of patients affected by chronic myeloid leukemia, allowing long-term improvement in overall survival and deep molecular responses. TKI treatment is also associated to an increased risk of cardiovascular event. The etiopathogenesis of this effects is not clear possibily due to a damage to the endothelial cell, the results of the interaction of genetical predisposition, risk factors and life style habit. The 9p21 region is the strongest genomic marker for cardiovascular disease that has been identified in multiple genome-wide association study. We retrospectively studied 182 patients affected by CML and treated with different TKIs for expression of polymorphism rs1333040C>T and rs7865618A>G of chromosome 9p21 in order to define the role of genetic cardiovascular risk profile to better tailor individualized treatment strategy and identify patients who require strict monitoring of additional risk factors during treatment. Patients and methods We analysed 182 CML patients in chronic phase. All patients were treated with either first, second or third generation TKIs. Patients were compared to a control group including 171 subjects. Genomic DNA was isolated from peripheral blood and the rs1333040C>T and rs7865618A>G polymorphisms were assessed by PCR-RFLP using the BsmI and MspI restriction endonucleases, respectively. Results Ninety-three out of 181 (51%) patients presented the C/T polymorphism, 82 (46%) presented T/T polymorphism and 6 (3%) patient presented wild type polymorphism C/C for rs1333040, test result was not evaluable in 1 patient. Eighty-five out of 181 (47%) patients presented the G/A polymorphism, 73 (40%) presented A/A polymorphism and 23 (13%) patient presented wild type polymorphism G/G for rs7875618 . Test result was not evaluable in 1 patient. The distribution of polymorphism C/C for rs1333040 and G/G for rs7875618 were statistically different compared to control group (p0.0004 and p0.0136 respectively) as showed in table 1. In a sub-analysis, including only 93 patients, a significantly higher incidence of cardiovascular events according to genotypes of SNP rs 1333040 was observed. In C/T group (54 patients) we retrospectively observed 3 cardiovascular events (5.55%) : 2 were transient ischemic attack (TIA) before the diagnosis of CML occurring in 2 female patients aged 69 and 73 respectively and a peripheral arterial obstructive disease (PAOD) in a female patient ,aged 74, with a baseline CAD score of 10, receiving nilotinib 800 mg/d as third line treatment. In T/T group (39 patients) we retrospectively observed 9 (23.1%) cardiovascular events at a median age of 60 years (range 44-82) and with a median estimated cardiovascular risk of 8 (range 0-20) Six patients developed a myocardial acute infarction (AMI) during treatment with TKIs, but 5 out of six had a previous history of AMI. One patient presented a TIA after history of previous of AMI. All patients with previous history of AMI were receving antiplatelets agents. One patient developed PAOD during first line treatment wih nilotinib and one developed an distal arteriopathy associated to an erectile dysfunction. The different incidence of cardiovascular events according to genotypes (T/T vs C/T ) was statistically significant by Fisher'sTest (p=0.0248). Discussion The role of 9p21 region , in particular the genes located in proximity of a noncoding RNA sequence named ANRIL, could be a useful guide for the prophylaxis of cardiovascular events during TKI therapy. Table 1 genotypes distribution between CML patients and controls rs1333040 rs7865618 Patients 82 93 6 23 85 73 46% 51% 3% 13% 47% 40% Controls 62 84 25 8 77 86 36% 49% 15% 5% 45% 50% p=0.0004 P=0.0136 Disclosures Bacigalupo: SANOFI: Speakers Bureau; PIERRE FABRE: Speakers Bureau.

Abstract 2770 In the “real world” of clinical practice, often physicians choose to treat very elderly CML patients with imatinib (IM) at lower than standard (400 mg/day) dose, but there are no published data on the results. To highlight this issue, we retrospectively revised 200 > 75 years old CML patients in chronic phase treated with IM 29 haematological Italian Institutions. We compared 58 patients (29%) who received low-dose IM (≤ 300 mg/day) according to physician decision (LD group) with the remaining 142 patients (71%) who received standard dose IM (SD group). In the SD group, there were 73 males and 69 females with a median age at IM start of 77.9 years (IR 76.0–80.3), Sokal Risk at diagnosis was low in 3 patients, intermediate in 86, high in 39 and not evaluable in 12. Two or more concomitant diseases requiring specific treatments were present in 93/142 patients (65.4%), with 85 patients (59.8%) taking 3 or more concomitant drugs. Twenty-seven patients (19.0%) were in late chronic phase (≥ 12 months from diagnosis before starting IM); on the whole, median time from diagnosis to IM was 1.1 months (IR 0.5–3.0). In the LD group, there were 31 males and 27 females with a median age of 80.2 years (IR 77.9–84.5) at IM start, Sokal Risk at diagnosis was intermediate in 34 patients, high in 17 and not evaluable in 7. Two or more concomitant diseases requiring specific treatments were present in 43/58 patients (74.1%), with 43 patients (74.1%) taking 3 or more concomitant drugs. Fifteen patients (25.8%) were in late chronic phase; on the whole, median time from diagnosis to IM was 1.8 months (IR 0.7–10.4). Starting dose of IM was 300 mg/day in 44 patients (75.8%) and < 300 mg/day in 14 patients (24.2%). According to CTC-AE, grade 3–4 hematological and extra-hematological toxicities were observed in 29 (20.4%) and 30 (21.1%) patients in the SD group compared with 10 (17.2%) and 14 (24.1%) patients in the LD group, respectively. Overall, 63 patients in the SD group (44.3%) required a dose reduction compared to 13 (22.4%) in the LD group (p=0.004): eleven (7.7%) patients in the SD group discontinued IM for toxicity compared to 13 (22.4%) in the LD group (p=0.004). Response to IM in the 2 groups is detailed in the table.SD groupLD grouppN° patients evaluable for response13656Early discontinuation8 (5.8%)8 (14.3%)0.054Resistant disease3 (2.2%)1 (1.8%)0.859Complete haematological response only24 (17.6%)12 (21.4%)0.527Partial cytogenetic response9 (6.6%)6 (10.7%)0.329Complete cytogenetic response92 (67.6%)29 (51.8%)0.052Major molecular response69 (50.7%)17 (30.3%)0.012 After a median follow-up of 33.7 months (IR 18.1–64.7), in the SD group 35 patients died (5 from disease progression and 30 from unrelated causes), 5 patients were lost to follow-up and 102 are still alive: in the LD group, 15 patients died (3 from disease progression and 12 from unrelated causes), 3 patients were lost to follow-up and 40 are still alive. In the SD group, 2-year and 5-year overall survival were 93.2% (CI95% 88.6–97.2) and 65.7% (CI95% 55.0–76.3), respectively; in the LD group, 2-year and 5-year overall survival were 89.7% (CI95% 80.4–98.9) and 67.0% (CI95% 49.6–84.4), respectively. In conclusion, in very elderly CML patients even reduced IM dose appears to be safe and effective enough to achieve sustained cytogenetic and molecular responses with prolonged overall survival. Therefore, also very elderly patients with co-morbidities should have this chance of cure without no upper age limit. Disclosures: Russo Rossi: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.

Abstract 1686 The Eutos score has recently been published as a new prognostic score in CML because of its prognostic ability and its simplicity in the imatinib era. It maintains the percent of basophils and the spleen size and it eliminates three other laboratory values and the variable of the age, that is usually important in the prognosis of almost all the diseases. This score was able to predict the probability of achieving a complete cytogenetic response (CCgR) within 18 months, which is the most solid and confirmed surrogate marker of survival in CML treated with imatinib. Thus we reviewed the cases of CML affecting individuals > 75 years and we apply the Eutos score and compare results with classic Sokal risk. We collected 221 patients from 29 of the major Italian hematological centers for diagnosis and treatment of CML. Because of the lack of data for the calculation of the scores in 84 patients, 137 patients were evaluable. The M: F ratio was 70: 67, the median age was of 78 years (range 75–89). Patients aged >75 years as expected showed frequently comorbidities (cardiovascular, respiratory, renal, oncologic ones). The distribution according to the Sokal score was: 3 patients in the low risk group, 95 patients in the intermediate risk group and 39 patients in the high risk group. As expected, there were only few patients in the low Sokal risk group aged >75 years in demonstration of the importance of the age in this score. Calculating Eutos score we have identified only 6 patients with a high score, whereas the remaining 131 patients were in the low risk group. The group with high Eutos risk score included 5 males and 1 female; their median age was 77 years (range 75–78), at the onset their median white blood cell count was 33.840/mmc (range 29.500–300.000), platelet count was 1.443.000/mmc (range 453.000–4.849.000), their median level of hemoglobin was 8.8 g/dl (range 7.7–13.9). All of them showed percent of basophils>12%, whereas at physical examination splenomegaly was usually moderate with no hepatomegaly. Due to the small sample of patients in the high Eutos score statistical analysis was not feasible but we tried to correlate baseline informations to the outcome. Not all the high Eutos risk patients were in the high Sokal risk group (3 patients were in the high Sokal risk group and 3 were in the intermediate one) none was in the low Sokal risk group. All but one patients in the high risk Eutos score were treated with imatinib in early chronic phase of CML. Then we considered the complete cytogenetic response (CCyR) at 18 months, performed through conventional cytogenetic analysis on bone marrow cells by G-banding technique. This has been chosen for the validation of the Eutos score as a solid early surrogate marker of outcome. The overall rate of CCyR was 100% in the low Sokal risk group, 63% in the intermediate Sokal risk group and 69% in the high Sokal risk group; the same type of response was 67% in the low Eutos risk group and 50% in the high Eutos risk group (Table 1). In the high Eutos risk group, 2 patients achieved CCyR, 1 patient achieved MMR, 2 patients did not achieve it and 1 patient was not evaluable. Two patients died because of comorbidities (relapse of colon cancer and cardio-respiratory insufficiency) at 19 and 39 months of follow up. Resistance to imatinib was registered in 17 out of 131 patients (13%) in the low Eutos risk and in 3 out of 6 patients (50%) in the high Eutos risk. In our series of CML patients >75 years, high Eutos score was infrequent (4.38%). Moving from Sokal to Eutos score, patients were largely reallocated as low risk Eutos score. It is not clear whether the low frequency of high risk Eutos might be attributed to a early diagnosis of CML in this subset of patients with age-related comorbidities requiring frequent laboratory exams. In view of the ability to predict CCyR at 18 months, Eutos score validation in the setting of elderly patients with CML could be relevant to clinical practice.Table 1Distribution of patients according Sokal and Eutos scoreN° patients% CCyRSOKALLow risk3100%Intermediate risk9563%High risk3969%EUTOSLow risk13167%High risk650% Disclosures: Russo Rossi: Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria.