ALBERT

Description: Background. High rates of response and minimal residual disease (MRD) negativity have been reported with the use of novel treatment options in multiple myeloma (MM) patients (pts) eligible for autologous stem-cell transplantation (ASCT). Despite very promising results, there is still a proportion of pts who do not respond to therapy or relapse early. This represents an unmet medical need. Aim. To identify the main factors predictive of early relapse in the context of novel treatment approaches. Methods. Data from newly diagnosed MM (NDMM) pts ≤65 years enrolled in the FORTE trial were analyzed. The evaluated baseline standard clinical and biological features included: age, Hb, creatinine, tumor circulating plasma cells (PCpb) evaluated by flow cytometry, bone marrow plasma cells (PCbm) evaluated as continuous variables, free light chain (L vs K), M-component subtype (IgA vs others), Revised International Staging System (R-ISS II/III vs I), LDH (〉ULN vs ≤ULN), ISS (III vs II vs I), presence vs absence of chromosomal abnormalities detected by FISH [(del17p, t(4;14), t(14;16), t(11;14), amp1q, del1p, del13], and presence vs absence of plasmacytomas. Pts were randomized to receive carfilzomib, lenalidomide, dexamethasone (KRd) induction - ASCT intensification - KRd consolidation (arm A); KRd12 (arm B); and carfilzomib, cyclophosphamide, dexamethasone (KCd) induction - ASCT intensification - KCd consolidation (arm C). Thereafter, patients were randomized to maintenance with lenalidomide alone or lenalidomide plus carfilzomib. Pre-maintenance MRD evaluation was performed by 8-color second generation flow cytometry (sensitivity 10-5) in patients who achieved at least a very good partial response (VGPR). Early relapse was defined as relapse ≤18 months from randomization. Univariate feature selection was performed between both categorical and continuous baseline variables and the achievement of pre-maintenance MRD negativity, according to Chi-square and Kruskal tests. The same baseline features, plus the achievement of MRD negativity, were included in a univariate analysis to select candidate predictors of early relapse. Selected features were then included in a multivariate logistic model. A multivariate analysis was performed to evaluate predictors of MRD negativity and early relapse. The model was adjusted for age and administered therapy. Results. 474 patients were enrolled in the trial. Baseline features were well balanced in the 3 arms. Predictors of MRD negativity (10-5): In univariate analysis, the baseline factors selected basing on the probability of achieving pre-maintenance MRD negativity were creatinine levels, ISS stage, R-ISS stage, del17p, PCbm (P=0.004) and PCpb. In multivariate analysis, including single variables not aggregated in R-ISS, increased creatinine levels (OR 0.48, 95% CI 0.25-0.94, P=0.03), increased PCbm (OR 0.95, 95% CI 0.91-0.99, P=0.01) and presence of del17p (OR 0.44, 95% CI 0.23-0.83, P=0.01) reduced the probability of achieving MRD negativity (Table). Predictors of early relapse: In univariate analysis, the main baseline factors selected basing on the risk of early relapse were LDH, ISS, R-ISS, PCbm, PCpb, del17p and achievement of MRD negativity. In multivariate analysis, R-ISS II/III vs I (OR 3.7, 95% CI 1.24-11, P

Description: Abstract 3783 The achievement of Complete Cytogenetic Response (CCyR, Ph+ cells 0%) with Imatinib (IM) treatment still remains a crucial objective in Chronic Myelogenous Leukemia (CML) patients. According to The European Leukemia NET guidelines, CCyR should be achieved within the 12th month of treatment. To address the incidence and prognostic role of a very early achievement of CCyR, we revised 150 chronic phase CML patients [M/F 75/75, median age 56.6 years, interquartile range (IR) 41.8 – 68.4] treated with front-line IM at our Institution from June 2002 to December 2010 who had evaluable karyotype after 3 months of treatment. At onset, median WBC and PLT counts were 75.9 × 109/l (IR 35.3 – 125.5) and 402 × 109/l (IR 281 – 592), respectively. Sokal risk score was low in 72 patients (48.2%), intermediate in 68 (44.8%) and high in 10 (7.0%); a short pre-treatment phase (〈 3 months) with Hydroxyurea (HU) was administered to 132/150 patients (88.0%). Starting daily dose of IM was 400 mg in 133 patients (88.6%), 800 mg in 12 (8.0%) and 300 mg in 5 (3.4%). After 3 months of IM treatment, 118 patients (78.6%) achieved CCyR while 32 patients (21.4%) still presented Ph+ metaphases (〈 33% 14 patients and ≥ 33% 18 patients) at cytogenetic analysis. At univariate analysis, factors with a negative prognostic impact on achievement of CCyR at 3 months were palpable spleen enlargement (p 100.0 × 109/l at onset (p 65 years, Sokal risk score, PLT count 〉 500 × 109/l at onset and pre-treatment with HU did not appear to affect early CCyR achievement. Among the 118 patients in CCyR after 3 months, there were 12 failures (10.1%) during subsequent follow-up (2 suboptimal responses for molecular resistance, 7 cytogenetic relapses, 2 molecular relapses and 1 evolution to blastic phase); among the 32 patients who did not achieve early CCyR, there were 18 failures (56.2%) during subsequent follow-up (12 primary cytogenetic resistances and 6 cytogenetic relapses). The difference in the incidence of failures during follow-up in the 2 groups was highly significant (p

Description: Dasatinib is a 2nd generation tyrosine-kinase inhibitor active in CML patients resistant or intolerant to Imatinib; at present there is no data on its toxicity and efficacy in elderly patients. To highlight this issue, 37 patients treated with Dasatinib when aged 〉 60 years were retrospectively evaluated. There were 21 males and 16 females, median age at Dasatinb was 69.3 years (IR 64.9–73.0), Sokal Risk at diagnosis was low in 13 patients, intermediate in 14, high in 5 and not valuable in 5. Twenty-two patients (59.4%) were primary resistant, 4 (10.8%) intolerant and 11 (29.8%) secondary resistant to Imatinib; all but 2 patients were in CP when Dasatinib was started. Median time from diagnosis to Dasatinib treatment was 99.2 months (IR 56.8–124.5); 25/37 patients (67.5%) have been pretreated with IFN ± Ara-C before Imatinib, all patients received Imatinib at standard dose (400 mg/day) followed in 20/37 (54%) by Imatinib at increased dose (600–800 mg/day) with an overall median period of Imatinib treatment of 52.8 months (IR 26.2–60.9). In addition, 7/37 patients (18.9%) received other 2nd line treatment (3 with Nilotinib, 2 with Imatinib + HU and 2 with other drugs) before Dasatinib. Starting dose of Dasatinib was 140 mg/day in 18 patients and 100 mg/day in 19 patients, respectively. After a median period of treatment of 9.4 months (IR 3.0–19.1) all patients were evaluable for toxicity; among 18 patients receiving 140 mg, grade 3–4 haematological and extra-haematological toxicities were reported in 14 (77.7%) and 6 (33.3%) patients, respectively; among 19 patients receiving 100 mg, grade 3–4 haematological and extra-haematological toxicities were reported in 4 (21.0%) and 1 (5.2%) patients, respectively. Pleuro-pericardial effusions occurred in 3 patients, all treated with 140 mg as starting dose. Overall, 3/37 patients (all treated with 140 mg) discontinued permanently Dasatinib due to early toxicity; a dose reduction was needed in 17/37 patients [16/18 (88.8%) treated with 140 mg and 1/19 (5.2%) with 100 mg]. As to response, 28 patients were considered evaluable (≥ 6 months of treatment) and 9 considered as too early; five patients (17.9%) did not have any response (including 3 patients with early Dasatinib discontinuation for toxicity) and 23 (82.1%) achieved Complete Haematological Response (CHR). Furthermore, 11/28 patients (39.2%) achieved a Cytogenetic Response (CyR) (Major CyR in 4 and Complete CyR in 7) and 4/28 patients (14.2%) achieved a molecular response. In conclusion, Dasatinib, when employed at the current recommended starting dose of 100 mg/day; seems effective and very well tolerated also in heavily pretreated elderly subjects; these results are encouraging also for a future use of this drug in early chronic phase elderly patients.

Description: Median age of patients with CML is about 65 years, according to SEER 2000–2005 data. However, the treatment with Imatinib in elderly has been seldom specifically addressed: in particular, there is a lack of data regarding very elderly CML patients. To highlight peculiar aspects of toxicity and efficacy of Imatinib in this subset which accounts for at least 10–15% of all CML cases, we revised retrospectively 28 CML patients treated with Imatinib when aged 〉 75 years from 4 haematological Institution in Rome; there were 12 males and 16 females, median age at Imatinib was 78.7 years (IR 75.8 – 82.9), Sokal Risk at diagnosis was intermediate in 20 patients, high in 6 and not valuable in 2. One or more concomitant diseases requiring specific treatments were present in 26/28 patients (92.8%), with 15 patients (53.5%) assuming 3 or more concomitant drugs. Nine patients (32.1%) have been pretreated ≥ 6 months with HU before starting Imatinib; on the whole, median time from diagnosis to Imatinib was 1.8 months (IR 0.7 – 25.1). Starting dose of Imatinib was 400 mg/day in 23 patients (82.1%) and 300 mg/day in 5 patients (17.9%); overall, 15 patients (53.5%) (14/23 at 400 mg starting dose and 1/5 at 300 mg starting dose) needed a dose reduction and 6 (21.4 %) discontinued Imatinib for toxicity (early toxicity in 4 and late toxicity in 2). Excluding the 4 patients who discontinued Imatinib due to early toxicity, maximum tolerated daily dose during treatment was 400 mg in 8 patients, 300 mg in 13 patients and 200 mg in 3 patients. According to CTC-AE, grade 3 – 4 haematological and extra-haematological toxicities were observed in 7 (25%) and 12 (42.8%) patients, respectively; 2 patients (7.1%) presented a pleural effusion during Imatinib treatment. All patients were fully evaluable for response to Imatinib, with a median treatment period of 30.6 months (IR 15.7 – 49.2); six patients (21.4%) failed any response, (including 4 patients who discontinued Imatinib due to early toxicity) and 22 (78.6%) achieved a complete haematological response (CHR). Among these 22 patients in CHR, 4 refused any other karyotipic or molecular evaluation (3 are still alive in CHR, 1 died in CHR from unrelated cause after 44,5 months) and 17/18 (60.7% of all 28 patients) achieved a cytogenetic response (CyR), major in 1 patient and complete in 16 patients. In addition, 7 patients (25% of all 28 patients) achieved a complete molecular remission, with an undetectable BCR/ABL hybrid gene at qualitative nested PCR. In conclusion, Imatinib at reduced daily dose of 300 mg seems a relatively safe and quite effective treatment for very elderly CML patients; from our data, no upper age limit should be given for TKinhibitors treatment but also very elderly (and with concomitant severe diseases) patients should have this chance of cure.

Description: Conventional cytogenetics and molecular analyses allow to stratify acute myeloid leukemia (AML) patients into subgroups with different clinical and prognostic relevance. AMLs with unsuccessful cytogenetics and no known recurrent mutations are a subgroup of cases for which information on possible underlying genetic lesions of the leukemic cells is lacking and with a poorly defined outcome. Previous studies have quantified the rate of unsuccessful karyotyping in approximately 10% of the analyzed AML samples and it is conceivable that if cases with molecular rearrangements were to be included this figure could be lower. With the aim of investigating the prevalence and impact of cases with an undefined genetic profile (UGP), we studied 437 AML patients - 228 males and 209 females, with a median age of 50 years (range 1-81) - treated on successive intensive chemotherapy protocols at our Institution. Conventional cytogenetic and molecular analyses - RUNX1-RUNX1T1, CBFB-MY11, DEK-NUP214, FLT3-ITD, NPM1, BCR-ABL, MLL-PTD - were performed at diagnosis. According to the genetic alterations, patients were comprehensively stratified into three subgroups: a favorable risk group - t(8;21) RUNX1-RUNX1T1, inv(16) CBFB-MY11, normal karyotype with mutated NPM1 without FLT3-ITD - with a 5-year overall survival (OS) of 65%, an intermediate risk group - normal karyotype with mutated or wild type NPM1 and FLT3 ITD or wild-type NPM1 without FLT3-ITD, t(9;11)(p22;q23), cytogenetic abnormalities not classified as favorable or adverse - with a 5-year OS of 27% and an unfavorable risk group - inv(3)(q21q26) or t(3;3)(q21;q26), t(6;9)(p23;q34), DEK-NUP214, t(v;11)(v;q23), -5 or del(5q), -7, complex karyotype - with a 5-year OS of 11%. Thirty-three patients (7.5%) were identified as having an UGP and their baseline characteristics, as well as clinical outcome, were compared to those of patients with defined molecular and cytogenetic features. Patients with an UGP were older at the onset of the disease than those with a delineated genetic profile (median 55 vs 49 years). In addition, the proportion of UGP cases increased with age, being 3% in patients 50 years. The complete remission (CR) rate for UGP patients (69.6%) was similar to that of intermediate risk patients (71.1%), but inferior to that of patients with a favorable risk profile (90.5%) (p=0.0046) and better than that of unfavorable genetic risk patients (63.7%). After adjusting for age, gender, WBC and platelet count, Hb, marrow blast percentage at diagnosis and treatment, UGP remained an independent factor for lower CR rate with respect to patients with a favorable genetic risk profile. The frequency of relapse was significantly higher in patients with UGP compared to the favorable risk group (60.8% vs 32%) (p=0.011). In multivariate analysis, the 5-year OS of patients with UGP was significantly worse than that of patients with a favorable genetic risk profile (p

Description: Introduction Lenalidomide (Len) and low-dose Dexamethasone (dex) (Rd) in continuous is a new standard of care for elderly newly-diagnosed multiple myeloma (NDMM) patients (pts), as established by FIRST trial (Facon et al, Blood 2018). Methods and results This is a retrospective, multicentric study conducted in Italy with the aim of evaluating efficacy and tolerability of Rd in a real-life population. Thirty-seven centers were involved and data of 429 pts are available. Pts were considered eligible for the study when completing at least 2 cycles of Rd regimen. Table 1 summarizes the characteristics of pts at time of MM diagnosis. Median age was 78 years (range 57-92), 36.6% had an ECOG PS≥2, creatinine clearance (ClCr) was ULN (P=0.01) and ClCr2 still impact on OS (p

Description: Abstract 4271 The achievement of Complete Cytogenetic Response (CCyR) (Ph+ cells 0%) with Imatinib treatment still remains the most important objective in Chronic Myelogenous Leukemia (CML) patients. According to The European Leukemia NET guidelines, CCyR should be achieved within the 12th month of treatment while at 3 months of treatment the goal should be complete haematological response. To address the prognostic role of the early achievement of CCyR, we revised 108 chronic phase CML patients [M/F 57/51, median age 54.9 years, interquartile range (IR) 40.8 – 68.1] treated with front-line Imatinib at our Institution from June 2002 to June 2008 who had evaluable karyotype after 3 months of treatment. At onset, median WBC and PLT counts were 78.4 × 109/l (IR 34.0 – 135.9) and 399 × 109/l (IR 282 – 585), respectively. Sokal risk score was low in 52 patients (48.1%), intermediate in 49 (45.4%) and high in 7 (6.5%); a short pre-treatment phase (〈 3 months) with Hydroxyurea was administered to 94/108 patients (87%). After 3 months of Imatinib treatment, 84 patients (77.7%) achieved CCyR while 24 patients (22.3%) still presented Ph+ metaphases (median value 40%, IR 20 - 80) at cytogenetic analysis. At univariate analysis, factors with a negative prognostic impact on achievement of CCyR at 3 months were palpable spleen enlargement (p=0.002), WBC count at onset 〉 100.0 × 109/l (p=0.01) and pre-treatment with Hydroxyurea (p=0.032); on the contrary, sex, age, Sokal risk score and PLT value did not appear to affect early CCyR achievement. Among the 84 patients in CCyR after 3 months, there were 10 failures during follow-up (6 cytogenetic relapses, 2 molecular relapses and 2 evolution to blastic phase); among the 24 patients who did not achieve early CCyR, there were 12 failures during follow-up (9 primary resistances and 3 cytogenetic relapses). The difference in the incidence of failures during follow-up in the 2 groups was highly significant (p

Description: Background: The role of Minimal residual disease (MRD) as surrogate for survival in Multiple Myeloma (MM) patients is well established. Therefore, new response criteria recommend including Multiparameter Flow cytometry (MFC) and next generation Sequencing (NGS) MRD negativity (minimum sensitivity of 1 in 105 nucleated cell) to deeply characterize complete remission (CR) [Kumar SK, Lancet Oncol 2016]. Here we analyzed and compared MRD data from the FORTE trial both by MFC and NGS techniques. Methods: Newly diagnosed MM patients ≤65 years were randomized to receive carfilzomib, lenalidomide, dexamethasone (KRd) induction - autologous stem cell transplantation (ASCT) intensification - KRd consolidation (KRd_ASCT); KRd12 and carfilzomib, cyclophosphamide, dexamethasone (KCd) induction - ASCT intensification - KCd consolidation (KCd_ASCT). Thereafter, patients were randomized to maintenance therapy with lenalidomide alone or lenalidomide plus carfilzomib. MRD evaluation was performed by 8-color second generation flow cytometry (sensitivity 10-5) in patients who achieved at least a very good partial response (VGPR) before maintenance. In a subgroup of these ≥ VGPR patients, next generation flow (NGF; sensitivity 10-5 - 10-6) was performed. Moreover, in patients achieving ≥ CR, MRD pre-maintenance was also assessed by NGS (Adaptive Biotechnologies, Seattle, WA; sensitivity 10-5 - 10-6). Therefore, only patients achieving ≥ CR have both MFC and NGS evaluations, and we focused on this ≥ CR population to compare MRD results with the 2 techniques. Spearman's rank correlation coefficient was used to measure the concordance between MFC and NGS. Fisher or Pearson's Chi-squared tests were adopted, where appropriate, to evaluate the statistical significance, at the level of 0.05. Results: ≥ CR pre-maintenance was achieved in 233 patients enrolled in the trial; at data cut-off, MFC and NGS data were available for 176/233 (76%) patients who were included in this analysis (62 received KRd_ASCT, 65 KRd12 and 49 KCd_ASCT). Median age of this ≥ CR population is 57 years (IQR 52-62), 14% have International Staging System (ISS) III stage and 26% high risk cytogenetics by FISH features [either del(17p) or t(4;14) or t(14;16)] reflecting baseline clinical features of the entire FORTE population. 139/176 (79%) ≥ CR patients were MFC negative at a cut-off of at least 10-5. Rate of MRD negative MFC among ≥ CR negative in the 3 arms were: 53/62 (85%) in KRd_ASCT, 51/65 (78%) in KRd12 and 35/49 (71%) in KCd_ASCT, reflecting the higher rate of MCF MRD negativity pre-maintenance reported by ITT in the overall population in the 2 KRD arms [Gay F, ASH 2018]. NGS negativity at a cut-off of at least 10-5 was detected in 87/176 (49%) of ≥ CR patients. Rate of MRD negative NGS at least 10-5 among ≥ CR negative in the 3 arms were: 35/62 (56%) in KRd_ASCT, 31/65 (48%) in KRd12 and 21/49 (43%) in KCd_ASCT. NGS negativity at a cut-off 10-6 was detected in 34/123 (28%) of ≥ CR patients (for 53/176 CR patients 10-6 sensitivity was not reached). Rate of MRD negative NGS at least 10-6 among ≥ CR negative in the 3 arms were:14/41 (34%) in KRd_ASCT, 10/44 (23%) in KRd12 and 10/38 (26%) in KCd_ASCT. Thereafter, we have analyzed the concordance between MRD results by the two techniques. Overall (samples at 10-5 and 10-6 sensitivity), Spearman's coefficient is 0.63 (p 〈 0.001); discordances between the two methods have been observed in 54/176 paired samples (30%). In particular, 53 samples (30%) are NGS positive but MFC negative, of which 34/53 (64%) have reached 10-6 sensitivity by NGS. Only 1 MFC positive sample is NGS negative. In a subgroup of patients evaluable both by NGS and NGF (26 paired samples, sensitivity 10-6), Spearman' s coefficient is 0.83 (p 〈 0.001), although a higher sample size is needed to confirm these preliminary concordant results. Conclusion: In patients who achieved ≥ CR, rate of at least 10-5 MRD MCF negativity was 79% and rate of at least 10-5 NGS negativity was 49%. Assessment both by MFC and NGS showed a good concordance, particularly if the same sensitivity is reached. Longer follow up is needed to assess the impact of MFC in comparison with NGS on patients' outcomes, particularly to evaluate if 10-6 NGS or NGF sensitivity may provide further clinical information, possibly identifying patients with very long survival or potentially cured. Disclosures Oliva: Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Belotti:Janssen: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Galli:Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Leadiant (Sigma-Tau): Honoraria; Janssen: Honoraria; Celgene: Honoraria. Offidani:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vozella:Amgen: Honoraria; Celgene: Honoraria. Zambello:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Kirsch:Adaptive Biotechnologies: Employment. Jacob:Adaptive Biotechnologies: Employment, Other: shareholder. Ballanti:Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Celgene: Honoraria. Corradini:Roche: Honoraria; Sanofi: Honoraria; KiowaKirin: Honoraria; Kite: Honoraria; Novartis: Honoraria, Other: Travel Costs; BMS: Other: Travel Costs; Servier: Honoraria; Takeda: Honoraria, Other: Travel Costs; Gilead: Honoraria, Other: Travel Costs; AbbVie: Consultancy, Honoraria, Other: Travel Costs; Amgen: Honoraria; Celgene: Honoraria, Other: Travel Costs; Daiichi Sankyo: Honoraria; Jazz Pharmaceutics: Honoraria; Janssen: Honoraria, Other: Travel Costs. Omedé:Janssen: Membership on an entity's Board of Directors or advisory committees. Cavo:takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto:Amgen: Honoraria; Celgene: Honoraria. Boccadoro:Sanofi: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; AbbVie: Honoraria; Mundipharma: Research Funding. Gay:AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: The presentation includes discussion of off-label use of a drug or drugs for the treatment of multiple myeloma.

Description: The DASISION and ENESTnd controlled clinical trials have changed the front-line treatment of Chronic Myelogenous Leukemia (CML) leading to the advent of dasatinib and nilotinib in this setting: however, both these company-sponsored trials had many exclusion criteria, with a possible selection bias compared to the real-life CML population. To address the impact of these exclusion criteria on the 1st line treatment in the current clinical practice, we revised 207 unselected newly diagnosed chronic phase CML patients [M/F 108/99, median age 58.8 years, interquartile range (IR) 42.3 – 70.2] treated with front-line imatinib from June 2002 to June 2013 at our Institution and evaluated how many of them would have been excluded from enrolment in the 2 trials. Among these 207 patients, 28 patients should have been excluded by both trials due to polycomorbidities (12 cases), severe cardiopathy (5 cases), age 〉 80 with frailty (3 cases), drug abuse (2 cases), severe liver impairment, Rendu-Osler disease, active prostatic cancer, chronic obstructive broncopulmonar disease (COPD) + peripheral arterial obstructive disease (PAOD), COPD + arrhythmia, refusal to any marrow examination (1 case each). In addition, 8 patients should have been considered not eligible only for the DASISION due to isolated COPD and 19 patients should have been considered not eligible only for the ENESTnd due to isolated diabetes (10 cases), arrhythmia (4 cases), acute myocardial infarction 〉 6 months before CML diagnosis (2 cases), chronic pancreatic disease (2 cases), PAOD (1 case). On the whole, 36/207 patients (17.4%) would have been considered not eligible for the DASISION trial and 47/207 (22.7%) for the ENESTnd trial. As expected, these patients potentially not eligible for DASISION and ENESTnd were significantly older and with the imatinib treatment had a worse follow-up in terms of Complete Cytogenetic Response (CCyR), Major Molecular Response (MMolR) and Overall Survival (OS) compared to patients potentially eligible, as shown in the Table. In conclusion, our data highlight that an important fraction of newly diagnosed patients in a real-life setting would have been excluded by the 2 controlled trials whose results are the current mainstay of the 1st line treatment in CML: thus, an automatic transposition of those results into the current clinical practice should be regarded with caution. Disclosures: No relevant conflicts of interest to declare.

Description: Azacytidine (AZA) is a demethylating agent widely used in the treatment of patients with high-risk Myelodysplastic Syndromes (MDS). Pulmonary infections are often reported in these patients during AZA treatment, however, their incidence, etiology and impact in the overall outcome are still unclear. A major problem is represented by the low level of clinical and microbiological documentation, as most of patients treated with AZA are managed on an outpatient basis. This study aims to evaluate the incidence and clinical impact of pulmonary infections in MDS patients treated with AZA in 5 hematological Institutes in Rome, with a relatively homogeneous infective diagnostic work-up in the presence of fever or other infective clinical signs. We retrospectively evaluated 146 MDS patients [M/F 93/53, median age 69.5 years, interquartile range (IQR) 65.0 - 75.6] treated with AZA at our Institutions from 04/2009 to 01/2016. All patients received AZA cycles at standard dosage (75 mg/m2 for 7 days every 28 days) as outpatients. In the event of febrile neutropenia or other infectious episodes patients underwent blood cultures, culture from other sites, and chest x-ray or (preferably) pulmonary CT-scan. Galactomannan assay from serum and from sputum/bronchoalveolar lavage was performed as indicated. The total number of AZA cycles was 1712, with a median per patient of 9 cycles (IQR 5 - 17 cycles). There were 75 episodes of lung infection (4.1% of AZA cycles), with 58 patients (39.7%) presenting at least 1 episode. Based on the above diagnostic work-up, pulmonary infiltrates were considered of fungal origin in 21 cases (28.0%), associated to bacteremia in 5 cases (6.7%) and of unknown origin in the remaining 49 cases (65.3%). As to the time of occurrence of lung infections, 29 episodes were documented in the first 4 cycles of AZA treatment (5.4% of 535 cycles) and the remaining 46 episodes beyond the 4th cycle of AZA treatment (3.9% of 1177 cycles). Overall, a pulmonary fungal disease was documented in 10 of 535 (1.9%) cycles 1-4 and in 11 of 1177 (0.9%) cycles beyond the 4th (p=0.001). Several clinical features (age, gender, Hb level, WBC and PLT counts, time from diagnosis) were evaluated as predictive factors for the occurrence of pulmonary infection, but none was significant. Out of 58 patients who developed at least one pulmonary infection, 39 (67.2%) definitively discontinued the AZA treatment within 3 months from the infectious episode due to deterioration of clinical conditions, hematologic disease progression and/or death. Attributable mortality rate of patients with pulmonary infection was 22.4% (13 of 58). The median Overall Survival (OS) of the whole cohort was 18.0 months (95%CI 14.4 - 21.5): the median OS of patients with pulmonary infection was 15.6 months (95%CI 13.1 - 18.0) compared with 21.5 months (95%CI 16.3 - 26.6) of patients without pulmonary infection (p=0.031). In conclusion, pulmonary infections are a common complication in MDS patients receiving AZA treatment, and are often associated to an interruption of AZA therapy. Pulmonary fungal infections are more frequently observed early during the first cycles of treatment. It should be defined if the poor outcome of patients who develop pulmonary infections during AZA therapy is an epiphenomenon of an immunologic deterioration associated to the hematologic disease progression or is independently related to the complication. If confirmed in other experiences, the results of our study raise the issue of the need of an antibacterial and/or antifungal prophylaxis particularly during the first months of AZA therapy. Disclosures Latagliata: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Janssen: Consultancy, Honoraria; Shire: Honoraria. Breccia:Celgene: Honoraria; Novartis: Consultancy, Honoraria; Ariad: Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.