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  • American Society of Hematology  (12)
  • 1
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 4153-4153
    Abstract: Background: Successful tyrosine-kinase inhibitors (TKIs) discontinuation has been obtained in some patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML). Careful molecular monitoring after discontinuation is the key to guarantee the safety, in terms of prompt resumption of therapy according to retreatment threshold criteria. It was observed that the majority of relapses usually occur during the first 6 months after TKI discontinuation [Saussele S, Lancet Oncol 2018; Etienne G, JCO 2017], accounting for the monthly quantitative PCR (qPCR) that all prospective protocols included in the trial design at least during the first half-year. Two studies [Kong HJ, Cancer 2017; Shanmuganathan N, Blood 2019] investigated if performing molecular analysis with a different and less "cautious" timeframe yields comparable efficacy with logistical issues reduction. Here we retrospectively evaluated how molecular monitoring has been conducted in Italy on a cohort of patients not included in any prospective trial with follow-up visits. Methods: The outcome of Italian patients with CP-CML who discontinued TKIs per clinical practice has recently been reported [Fava C, Haematologica 2019]. For the purpose of the present study, all the 32 participating centers were required to provide dates and molecular results available for each enrolled patient in the first 24 months after TKI stop. Descriptive analysis was carried out. The average time to the loss of major molecular response (MMR), the frequency of the visits (monitoring) and the occurrence of loss of MMR within the first 6 months, between 6-12 months, and 13-24 months were computed. When appropriate non-parametric tests were used to test for differences. Results: 227 chronic phase CML pts were included in this sub-analysis. Median age at TKI discontinuation was 58.73 years and median follow up since TFR was 2.03 years. In this timeframe every patient had a mean of 7.95 appointments for molecular evaluation. Overall, 1804 analysis were performed, of which 18.2% happened in the first three months and 38.2% in the first six months. During the first three months of TKI discontinuation, 40 pts (17.6%) didn't have any molecular assessment; 78 pts (34.4%) had only 1 qPCR performed, 77 pts (33.9%) 2 qPCR, 31 pts (13.7%) 3 qPCR and 1 pt (0.4%) 4 qPCR. For the first six months after TKI stop, 7 pts (3.1%) didn't undergo any BCR-ABL1 evaluation; 37 pts (16.3%) had only 1 analysis, 60 pts (26.4%) 2 analysis, 37 pts (16.3%) 3 analysis, 28 pts (12.3%) were evaluated 4 times, 40 pts (17.6%) 5 times, 17 pts (7.5%) 6 times and only 1 pt (0.4%) 7 times. The majority of visits fell between the 3rd and the 7th month after TKI interruption (Figure 1) with 84 pts (52.2%) being evaluated at month 3, 96 pts (59.6%) at month 4, 80 pts (49.7%) at month 5, 89 pts (55.3%) at month 6, 101 pts (62.7%) at month 7. In the first six months the visits occurred with a mean interval of 1.44 months; between months 7-12 molecular evaluations were performed every 1.94 months; during the second year of discontinuation (months 13-24) every 2.89 months (p 〈 0.001). Seventy-one pts lost major molecular response (MMR) in a mean time of 5.56 months. As expected, 55 pts (77.5%) lost MMR during the first six months whereas 16 pts (22.6%) relapsed later on: 3 pts (4.2) relapsed during the first month, 7 pts (9.9%) after two months, 13 pts (18.3%) after three, 19 pts (26.8%) after four, 8 pts (11.3%) after five months and 5 pts (7%) at six months. Only 6 patients lost MMR after 12 months of follow-up in TFR. All patients regained at least MMR after TKI resumption, and no progression occurred. Finally, we evaluated the number of patients who would experience a delay in the diagnosis of MMR loss if a three-months monitoring schedule was adopted. In the first 6 months, 15 pts (27.3%) would have a one month delay, 22 (40%) a 2 months delay; 18 pts (32.7%) would have a right timing. Very few patients would experience a delay in the following months (Figure 2). Discussion: The safety of TFR relies consistently on the management of patients off-therapy especially during the first 6 months, when molecular relapses more often occur. Our retrospective analysis showed that a less intense frequency of monitoring did not affect the success of TFR nor put pts at risk of progression. However, these data confirm that the first 6 months off-treatment require a more stringent follow-up for early detection of MMR loss. Disclosures Rosti: BMS: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Castagnetti:Novartis: Honoraria; Incyte: Honoraria; Pfizer: Honoraria; Bristol Myers Squiib: Consultancy, Honoraria. Capodanno:Novartis: Honoraria; Incyte: Honoraria. Ferrero:Novartis: Honoraria. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Elena:Pfizer: Consultancy; Novartis: Consultancy. Breccia:Pfizer: Honoraria; Celgene: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria. Iurlo:Novartis: Other: Speaker Honoraria; Pfizer: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria. Bocchia:BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Lunghi:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Cedrone:BMS: Honoraria; Novartis: Honoraria. Sgherza:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria. Santoro:Pfizer: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Giai:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Caocci:Novartis: Honoraria; Celgene: Honoraria. Levato:Incyte: Honoraria; BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Pfizer: Consultancy; Novartis: Consultancy. Saglio:Pfizer: Consultancy; Celgene: Consultancy; Incyte: Consultancy; Jansen: Consultancy; Ariad: Consultancy; Novartis: Consultancy; BMS: Consultancy. Fava:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria; Incyte: Honoraria.
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  • 2
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 4861-4861
    Abstract: Introduction Cytomegalovirus (CMV) infection is one of the most common complication after allogeneic hematopoietic stem-cell transplantation (HSCT) still associated with significant morbidity and mortality. Although pre-emptive therapy (PET) are routinely used in treatment of CMV after SCT, their prophylactic use is limited by clinically unacceptable myelosuppression and nephrotoxicity. Letermovir, available since 2019 in Italy, is the first antiviral agent approved by FDA and EMA which is indicated for the prophylaxis of CMV infection in CMV seropositive (R+) patients undergoing SCT. Presently, cost and drug interactions are the main disadvantages of Letermovir use. We performed a single-center observational retrospective study to evaluate the efficacy of primary Letermovir prophylaxis for CMV infection among high-risk patients (R+) receiving HSCT from serological negative donor (D-). Methods We evaluated a cohort of R+/D- patients transplanted from January 2017 to December 2020 (86/235 transplanted patients): among those eligible for Letermovir prophylaxis (N=70), 29 patients (transplanted after 2019) received Letermovir until day +100, whereas 41 patients (the historical control group transplanted before 2019) received CMV PET only in case of increased viral load (CMV reactivation). Patients unable to take oral therapy at day +7 from HSCT or assuming drugs for concomitant clinical conditions bringing about major pharmacokinetic interaction were excluded (N=16). We compared day +100 and day +200 cumulative incidence of clinically significant CMV infection (CS-CMVi), defined according to drug registration trial: Letermovir discontinuation before day +100, CMV reactivation (CMV-DNAemia leading to PET), CMV tissue invasive disease, disease relapse and death from any causes. Survival functions between groups were estimated by the Kaplan-Meier method and compared using log-rank test. Moreover, the overall survival (OS), disease free survival (DFS), non-relapse mortality (NRM) and cumulative incidence of II-IV grade acute graft-versus-host disease (aGVHD) was compared in the two cohorts. Finally, we analyzed the number of accesses in day hospital from initial discharge to day +180, as an indirect cost-effectiveness evaluation of letermovir prophylaxis. Results No severe adverse events related to the therapy were observed in the letermovir group. Letermovir prophylaxis started at a median of 11 days (range, 5-27) after HSCT. The median duration of Letermovir administration was 89 days (range, 40-113). The only early stop was due to patient death, not related to CMV or drug toxicity. CS-CMVi at day +100 occurred in 13.8% vs 61.0% in letermovir and historical group, respectively (p & lt;0.001). Of note, none of the events in letermovir group was related to CMV reactivation whereas 24/25 in the historical group were. A trend toward lower CS-CMVi in the letermovir group was observed also at day +180 (44,8% vs 65,9%, p =0.080), with 6 late reactivations in patients who received prophylaxis. Moreover, at follow-up one patient in the experimental group and 3 in the control group developed CMV disease. Of note, in vivo T-cell depletion was used in 86% of patients in letermovir and 83% in historical group, and most of the CMV reactivations occurred after development of aGVHD: in 83% and 54% of patients, respectively. No differences in OS and DFS were observed between the two cohorts. Finally, a trend toward lower number of day hospital admissions was shown in patients who received letermovir prophylaxis (median 2 admissions, IQR 0-8, vs median 4.5, IQR 0-16), suggesting higher quality of life and costs reduction. Conclusions Our real-life experience demonstrated the efficacy of Letermovir in reducing the incidence of CMV reactivation. Longer follow-up is needed to clarify advantages in terms of disease-free and overall survival. Further studies are needed to investigate the role of prophylaxis beyond day 100 in high risk patients, such as those who receive a T-depleted transplant or who develop aGVHD. The role of Letermovir prophylaxis on immuno-reconstitution and its cost-effectiveness remains to be evaluated. Disclosures Marco: Jazz: Consultancy; Insight,: Consultancy; Janssen: Consultancy. Ferrero: EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Clinigen: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau.
    Type of Medium: Online Resource
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    Publication Date: 2021
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  • 3
    In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1498-1500
    Type of Medium: Online Resource
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    Publisher: American Society of Hematology
    Publication Date: 2022
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  • 4
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 4446-4446
    Abstract: Abstract 4446 Life expectancy of CML patients has greatly improved in tyrosine-kynase inhibitor (TKI) era, but still some questions remain about the management of suboptimal responders (SR) to imatinib standard dose. This group of patients appears to be heterogeneous, with significant differences in terms of event-free survival between cytogenetic SR and molecular SR (Alvarado et al, Cancer 2009) European Leukemia Net (ELN) recommendations did not clarify those differences and there isn't a clear agreement on SR: maintaining imatinib at standard or higher dose or switching to another TKI are all considered acceptable options (Baccarani et al, JCO 2009). We retrospectively analyzed 63 CML patients, diagnosed in chronic phase between 1988 and 2011, SR to imatinib 400 mg/d, treated according to the 3 different ELN options. Fifty-two patients received imatinib front line and 11 had been previously treated with an interferon based therapy. Sokal score, evaluable in 44 patients, was high in 7, intermediate in 24 and low in 12, respectively. Twenty-five patients were cytogenetic SR and 38 molecular SR. The median follow-up from diagnosis was 76 months (range 10–292). At suboptimal response detection 47 patients (74%) continued imatinib 400 mg/d (30 of them afterword switched to high dose imatinib or new TKI), 12 patients (19%) increased imatinib dose to 600 mg/d (7) or 800 mg/d (5) (8 of them later changed TKI) and only 4 patients switched immediately to new TKI. Twenty-three percent of the 47 patients who continued imatinib 400 mg/d obtained a stable complete cytogenetic response (CCyR) and major molecolar response (MMR) while 27% underwent to a failure. Globally thirty-tree SR patients increased imatinib dose, 36% at suboptimal response detection and 64% after a median of further 12 months of standard dose treatment (range 3–50): 48% of them obtained a durable CCyR and MMR. Twenty-six evaluable patients switched to new TKI (9 to nilotinib and 17 to dasatinib), 13 after high dose imatinib: 62% of the patients achieved a stable CCgR and MMR. Both high dose imatinib and new TKI were significantly more effective in achieving CCyR and MMR than maintaining imatinib 400 mg/d (p 〈 0,05). Considering separately the subgroup of cytogenetic SR patients, a stable CcyR has been reached by 35% of patients continuing imatinib standard dose, by 50% of the patients who increased imatinib dose and by the totality of the patients treated with new TKI (option significantly superior to the other two, p 〈 0,05). Among molecular SR, 26% of the patients obtained a stable MMR with imatinib 400 mg/d, 52% with imatinib 600 or 800 mg/d and 63% switching to new TKI. The difference was statistically significant between new TKI and imatinib 400 standard dose only (p 〈 0,05). Cytogenetic SR maintained at imatinib 400 mg/d had a higher risk of event (defined as loss of hematologic or cytogenetic response or death) compared to molecular SR (40% vs 5%, p 〈 0,01), although at the last follow-up, after a change in therapeutical strategy, no difference in response rate was detected between cytogenetic and molecular SR (68% vs 71%) in stable CCyR and MMR. Two patients progressed to accelerated phase (clonal evolution) but then obtained an optimal response after switching to new TKI; 2 patients died of unrelated disease. Among the 61 living patients, 71% was in MMR, 26% in CCyR only and 3% didn't reach CCyR (for these patients the efficacy of the therapeutic change is not evaluable yet). In our casistics cytogenetic SR had a higher risk of negative events than molecular SR, as reported in literature, although they obtained similar responses after changing therapeutic strategy. No clear advantage in maintaining imatinib 400 mg/d after suboptimal response was observed, since it led to a few optimal responses and was associated with a significant risk of treatment failure. Imatinib dose increment might represent a more reasonable option, at least for molecular SR. Considering the global casistic no significant difference in response rates were found between new TKI and high dose imatinib even if dasatinib and nilotinib showed a trend towards a superior efficacy in patients mostly unresponsive to the last option, suggesting that an earlier switch to new TKI might further increase the proportion of optimal responders. For cytogenetic SR the switch to new TKI brought better results than those obtained with high dose imatinib: therefore it seems to be the best choice in this subgroup of patients. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
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  • 5
    In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 1537-1537
    Abstract: Context. AML is an oligoclonal disease. Intratumoral genetic heterogeneity (ITH) is pervasive in cancers and has often been linked to poor outcome. Except in patients (pts) with complex karyotypes (Bochtler, J Clin Oncol 2013), the clinical relevance of ITH remains unknown in AML. We assessed ITH in a real-life AML cohort. Methods. Since Nov 2015, all newly diagnosed AML pts at our institution were analyzed by targeted sequencing with a 60-gene myeloid panel at an average depth of 815X. Variant Allele Frequencies (VAF) were adjusted for copy number variation to estimate Cancer Cell Fractions (CCFs) and rank mutations by decreasing CCFs. Mutations were segregated into different clones when distant by & gt;10% CCF. Ancestral (as opposed to secondary) mutations are defined as those belonging to the first clone (Figure). We could next derive for each pt the total number of clones and the ITH index, defined as the ratio of secondary to ancestral mutations (according to Turajlic, Cell 2018). Results. We studied 201 consecutive AML pts (median age 67 years, secondary AML 24%). The median number of mutations was 4 (range 0-12). Clonal heterogeneity ( & gt;1 clone) was found in 71% of pts with a median of 2 clones per pt (range 1-5). 140 pts received intensive chemotherapy (IC), 50 hypomethylating agents (HMA) and 11 best supportive care (BSC) only. Signaling (FLT3, NRAS, KRAS, KIT, JAK2, CBL, CSF3R, BRAF, NF1, PTPN11, RIT1, CALR and MPL, 60%), DNA methylation (DNTM3A, TET2, IDH1/2, 54%), NPM1 (29%), spliceosome (U2AF1, SRSF2, SF3B1, ZRSR2, PRPF8, 27.9%) and tumor suppressors (PHF6, TP53, WT1, 27.4%) were the most frequently mutated pathways. ELN 2017 risk category was favorable, intermediate, adverse and not evaluable in 35%, 27%, 35% and 3% of pts respectively. Increasing ITH was associated with a higher number of clones (p=0.001) and of mutations (p & lt;0.001). ITH was greater in pts with at least one mutation in histone modifiers (ASXL1, ASXL2, EZH2, KMT2A-PTD KMT2D, KDM6A, p=0.0004), cohesin (STAG2, RAD21, SMC3, SMC1A, CTCF, p=0.0018) or signaling (p=0.002) genes but was not affected by the presence of mutations in DNA methylation or spliceosome, tumor suppressor genes, transcription factors (RUNX1, CEBPA, ETV6, GATA2) or co-activators (BCOR, BCORL1, EP300, CREBBP), all p & gt;0.05. ITH was not different among ELN 2017 risk categories (p=0.15). ITH was independent of age, WBC count and type of AML (secondary vs de novo), all p & gt;0.2. There was no significant difference in the number of mutations (p=0.12), clones (p=0.58) or ITH indexes (p=0.38) according to IC/HMA/BSC treatment strategies. We next performed a preliminary analysis of the prognostic impact of ITH in the 140 pts treated with IC (median age 58y), with a median follow-up of only 12.5 months. 117 (84%) pts achieved CR and 32 (23%) were transplanted in first CR. Median event-free survival (EFS) was 18.7 vs 8.0 months in pts with adv and non-adv ELN risk, respectively (p=0.016). In univariate analyses, DNA methylation (p=0.04) and spliceosome (p=0.007) mutations were the two pathways predicting adverse outcome. The number of mutations (p=0.6) or of clones (p=0.8) had no impact on EFS. Pts with fewer secondary than ancestral mutations (ITH & lt;1, 'ITH low' group, n=64 [46%]) had a median EFS of 13.6 months vs 19.8 months in the 76 (54%) pts with ITH index ≥1 ('ITH high' group, p=0.067). In a multivariate Cox model accounting for age, log(WBC), ELN risk, AML type (secondary vs de novo), presence of DNA methylation and spliceosome mutations and ITH, ITH-high was identified as a significant predictor of improved EFS (HR=0.54, p=0.03), independently of older age (HR=1.02, p=0.07), adv ELN risk (HR=2.4, p=0.005) and higher WBC count (HR=1.27, p=0.004). Censoring at transplant in first CR did not affect this result. In 14 pts who relapsed after a median of 12.9 months since diagnosis with paired NGS at relapse, the number of clones significantly decreased at relapse (p=0.046). Conclusion. Our results confirm that most AMLs are oligoclonal. Surprisingly, higher ITH is not related to older age or secondary AML. Our preliminary results suggest that lower ITH translates into shorter EFS in pts treated with IC. Longer follow-up and/or increased pt numbers are warranted to determine whether NGS-based assessments of clonal heterogeneity can improve AML risk stratification. Figure. Figure. Disclosures Fenaux: Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2018
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  • 6
    In: Blood Advances, American Society of Hematology, Vol. 3, No. 24 ( 2019-12-23), p. 4280-4290
    Abstract: Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell’Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 & gt;10% at 3 and 6 months, & gt;1% at 12 months, and & gt;0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
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    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 7
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 2700-2700
    Abstract: Context . AML patients (pts) with a high number of drivers have a poor prognosis (Papaemmanuil, NEJM 2016). Whether this unfavorable outcome is caused by clonal heterogeneity or by a high mutational load in the dominant clone remains undetermined. So far, the prognostic impact of clonal heterogeneity in AML has only been studied in pts with complex karyotypes, where it worsens prognosis (Bochtler, JCO 2013). We addressed this question in a two-center cohort of AML pts treated with IC. Methods . We retrospectively evaluated AML pts treated with IC from 2 centers with targeted sequencing of a 43-gene myeloid panel (mean depth 1193X). Variant allele frequencies were adjusted for copy number variation to estimate Cancer Cell Fractions (CCFs). Clone size for each mutation was derived from differences in CCF, assuming a linear accumulation of mutations. Relative clone sizes were then used to derive the Shannon Index (SI), a standard metric of genetic diversity (Maley, Nat Rev Cancer 2017, Figure A). Pts with no gene mutation were not evaluable for SI. Pts with a single mutation have a SI of 0, with increasing SI corresponding to greater dispersal of clone sizes, and thus indirectly of CCFs. Results . We included 292 pts (median age 57y, 37% ELN-2017 adverse risk), 269 (92.1%) with ≥ 2 mutations. Median number of drivers, including both mutations and cytogenetic alterations (the latter defined as in [Papaemmanuil, NEJM 2016]) was 4. SI increased with the number of drivers (Figure B, p 〈 10-4). In bivariate analyses adjusted on the number of drivers, SI was higher in adverse risk (p=0.0007) but was not associated with age or type of AML (de novo vs secondary). Median follow-up and EFS were 26.9 and 18.9 months, respectively. In univariate analyses, an increasing number of driver lesions significantly worsened EFS (HR=1.11, p=0.011), while SI as a continuous variable had no impact (HR=0.89, p=0.3). In a multivariate Cox model, the number of drivers (HR=1.74, p=0.002) and SI (HR=0.58, p=0.001), both as continuous variables, had significant but opposite prognostic value independently of age 〉 60y (HR=1.48, p=0.022), WBC 〉 50x109/L (HR=1.74, p=0.005), and ELN 2017 adverse-risk AML (HR=1.74, p=0.001). There was no significant statistical interaction between number of drivers and SI. OS was also independently poorer in patients with higher number of drivers (HR=1.19, p=0.021) and with lower SI (HR=0.65, p=0.03) in a similar Cox model. Because of the positive correlation between the number of drivers and SI, but inverse prognostic role, we defined pts with high clonal diversity (132 [49.0%] of the 269 pts with ≥2 driver lesions) as those with a SI higher than the median value of SI of all AMLs with the same number of drivers (Figure B). In those 269 pts, median EFS was 11.3 months in pts (n=73) with ≥5 drivers vs 22.2 months in those with 〈 5 drivers (n=196, p=0.04). EFS was significantly shorter in pts with low clonal diversity (median 10.1 vs. 33.4 months in pts with high diversity, p=0.002). Combining these criteria defined 4 groups with significantly different outcome (log-rank p=0.004, Figure C). We then compared our estimation of SI with a 'true' SI accounting for further clonal variegation caused by branching and/or LOH in 29 pts with resolved clonal architecture (Hirsch, Nat Comm 2016). Estimated and 'true' SI were highly correlated (Pearson's correlation 0.73, p 〈 10-5), showing that our estimated SI captures most of the genetic heterogeneity of AML. We finally performed a validation analysis in a publicly available cohort of 1540 AML pts (Papaemmanuil, NEJM 2016). Median OS of pts with low clonal diversity was 20.7 months vs 33.7 months in those with high clonal diversity (p=0.004). In a multivariate Cox model of OS accounting for age 〉 60y, type of AML (de novo vs else) and ELN 2010 risk (FLT3 allele ratio not available for stratification per ELN 2017), the number of drivers (HR=1.17, p 〈 10-5) and SI (HR=0.82, p=0.012), as continuous variables, significantly affected OS in opposite ways. Conclusion . Our results confirm that a higher number of drivers worsens AML prognosis, but also demonstrate that conversely, higher clonal diversity, estimated with Shannon's Index, confers a better outcome. These findings are consistent with a simple model whereby both a higher driver load and a higher expansion of the most mutated clone independently worsen prognosis in AML. Measuring both clonal diversity and dynamics could improve AML risk stratification. Figure Disclosures Thomas: ABBVIE: Honoraria; INCYTE: Honoraria; PFIZER: Honoraria; DAICHI: Honoraria. Ades:Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Fenaux:Aprea: Research Funding; Jazz: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Boissel:NOVARTIS: Consultancy. Dombret:CELGENE: Consultancy, Honoraria; AGIOS: Honoraria; Institut de Recherches Internationales Servier (IRIS): Research Funding.
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    ISSN: 0006-4971 , 1528-0020
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    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 8
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 216-216
    Abstract: Introduction. The recent spread of the COVID-19 infection has represented an important challenge in the management of acute lymphoblastic leukemia (ALL) patients. Aims and methods. To investigate the incidence, features, source of contagion and outcome of patients with ALL who developed a COVID-19 infection, a survey was conducted among 34 hematology centers throughout Italy within the Campus ALL network. The period covered by the survey spanned from February 2020 to April 2021 and included 756 adult ALL patients actively followed during this time period. Results. Sixty-three of the 756 ALL patients (8.3%) developed a COVID-19 infection, with an equal distribution among the various regions. The majority of cases (90.5%) was recorded during the second wave of the pandemic, between September 2020 and April 2021. The source of the infection was nosocomial in 26 cases (41.3%), familial in 23 (36.5%), unknown in 13 (20.6%) and work-related in 1 (1.6%). The infected patients were prevalently male (n=43, 68.2%) with a similar distribution among age groups: 21 patients aged 18-35 years, 17 35-50, 15 50-65 and 10 older than 65. Seventeen patients (27%) had a diagnosis of T-ALL, 28 (44.4%) of Ph- B-ALL and 18 (28.6%) of Ph+ ALL. Thirty-six (57.1%) of the infected patients had no concomitant comorbidities, whereas 27 (42.9%) had one or more comorbidities. The infection was documented at the onset of the disease in 4 patients (6.3%), during induction in 10 (15.9%), consolidation in 13 (20.6%), chemotherapy maintenance in 11 (17.5%), after allogenic transplant in 15 (23.8%), during maintenance with tyrosine kinase inhibitors (TKI) treatment or off-treatment in 8 (12.7%) and at relapse in 2 (3.2%). Of the infected patients, 9 were asymptomatic, 10 had only isolated fever, 36 had respiratory symptoms and 8 presented other symptoms, including - but not limited to - ageusia and anosmia. As a consequence, management of the infection was variable: 29 (46%) patients did not require hospitalization, 28 (44.4%) were hospitalized in a COVID ward and 13 of them required respiratory assistance; finally, 6 (9.5%) patients were transferred to an ICU. Importantly, in 54 patients (85.7%) there were no sequelae, in 1 patient a pulmonary fibrosis was documented and in 1 patient the delay in treatment led to a relapse of the disease, while 7 (11.1%) succumbed to the infection. Finally, in 6 cases (9.5%) the infection was still ongoing at the time of the survey, and at the last update (July 2021) it had resolved in all. Since a key aspect in the management of ALL is the adherence to the timing of treatment, we also investigated if COVID-19+ patients stopped treatment during the infection. Out of the 42 evaluable patients (patients who had undergone an allogeneic transplant or were off-treatment were excluded from this analysis), ALL treatment was suspended in 28 (66.6%). Importantly, while in Ph+ ALL only very few patients stopped treatment (3/12), in Ph- B-ALL the majority did interrupt it (18/22, p & lt;0.001); likewise, also in T-ALL most patients suspended treatment (7/8). Conclusions. The incidence of SARS-CoV-2 infection in adult ALL patients in Italy over a 15 month period has been similar to that observed in the general population and has been recorded mostly during the second wave of the pandemic. The contagion was mainly nosocomial, suggesting that outward care should be pursued as much as possible in ALL. The infection was manageable, with 46% of patients not requiring any medical intervention and an overall death rate of 11%. Strikingly, in line with previous reports 1, it appears that Ph+ ALL patients were more manageable, with less treatment interruptions. These findings underline the advantage of the TKI-based induction/consolidation strategy without systemic chemotherapy in Ph+ ALL used in the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) protocols and further point to a possible protective role of TKIs in COVID-19-infected patients. Foà R et al, Br J Haematol. 2020;190(1):e3-e5 Disclosures Chiaretti: Incyte: Consultancy; novartis: Consultancy; pfizer: Consultancy; amgen: Consultancy. Bonifacio: Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Marco: Jazz: Consultancy; Insight,: Consultancy; Janssen: Consultancy. Curti: Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees. Delia: Gilead: Consultancy; Amgen: Consultancy; abbvie: Consultancy; Jazz pharmaceuticals: Consultancy. Forghieri: Jannsen: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Honoraria. Lussana: Amgen: Honoraria; Astellas Pharma: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 9
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1262-1262
    Abstract: Introduction: The outcome of patients with acute myeloid leukemia (AML) secondary to myelodisplastic syndrome (MDS) or therapy-related (t-AML) receiving conventional treatment and allogeneic stem cell transplantation consolidation (HSCT) is poor. CPX-351 is a new drug composed by liposomal encapsulated cytarabine and daunorubicin, at a fixed molecular ratio of 5:1. It showed superior results, compared to standard 3+7 induction, in a phase III trial (Lancet et al, JCO 2018) in patients affected by t-AML or AML with myelodisplasia-related changes and it is now commercially available for secondary AML (sAML). We recently published results from CPX-351 Italian Named (Compassionate) Use Program (CUP) which enrolled 73 elderly sAML patients (Guolo et al, Blood Cancer J. 2020) showing that CPX-351 is an effective induction regimen for high risk AML patients treated with a curative aim. With a limited follow up, our data suggested the good activity and tolerability of CPX-351. Good quality remissions with acceptable toxicity in the majority of patients was achieved and CPX-351 increased the feasibility of HSCT in a poor risk AML cohort. Scarce data are available on long term outcome of high risk patients receiving CPX-351 in the real life setting. Here we report the results from the extended follow up analysis of the Italian CUP. Results: Seventy three patients were enrolled between December 2018 and June 2019 in a compassionate use program (CUP) in 33 Italian Hematology Centers. Data collection began on July 2019 and included 71/73 patients (97.2%), enrolled in 31 Centers. As previously reported, median age was 65.5 years (52-79). Sixty-two (88%) patients had at least one relevant comorbidity upon enrollment. Six patients (9%) presented with ECOG 3-4 upon enrollment. With a median follow up of 22 months, median overall survival (OS) was 13 months (21.2 - 22.8 95% IC). Two-years OS was 28.6% in the whole cohort. In order to confirm the positive impact of HSCT in first complete remission (CR) and the correlation with the other variables, a landmark model was applied, including only patients alive and in CR at day 90. In landmark analysis, HSCT performed in first CR after CPX-351 was the only significant predictor of longer survival: median OS was not reached for patients transplanted in first CR Vs 12 months for patients who did not undergo HSCT, p & lt; 0.05, Figure1). Two-year OS for patients who received HSCT was 57.6% vs 15.8% for patients who did not undergo HSCT. Conclusions: Results from the extended follow up of Italian CPX-351 CUP confirm the good activity CPX-351 in such a difficult cohort as sAML. Two-year OS for transplanted patients is high despite the high median age, the high frequency of severe comorbidities in this real life cohort of patients and the high frequency of high risk AML. On the contrary, non-transplanted patients show a poor outcome, thus confirming that CPX-351 induction as an optimal bridge to transplant induction therapy. Figure 1 Figure 1. Disclosures Galimberti: Incyte: Speakers Bureau; AbbVie, Janssen: Honoraria, Other: Travel grants. Marco: Insight,: Consultancy; Jazz: Consultancy; Janssen: Consultancy. Fracchiolla: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Speakers Bureau. Tafuri: Roche: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Rossi: Novartis: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Pagano: Gilead Science, MSD, Pfizer, Basilea, Janssen, Novartis, Jazz Pharmaceutical, Cidara: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Gilead Sciences, MSD, Pfizer Pharmaceuticals, Astellas Pharma: Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 10
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 3408-3408
    Abstract: Blinatumomab (Blina) and inotuzumab (InO) have improved the outcome of relapsed/refractory B-lymphoblastic leukemia (R/R B-ALL). However, many patients (pts) relapse after these treatments and little is known on their outcomes after recurrence and re-treatment with subsequent immunotherapy. We hereby describe the clinical characteristics and outcome of 71 pts with R/R B-ALL treated with both Blina and InO in any sequence - Blina/InO or InO/Blina - at different disease recurrences. At diagnosis, the median age was 34 years (15-64) and the male/female ratio was 1.6. Sixteen pts (22%) were Ph+ ALL, 3 (4%) were t(4;11)+ and 9 (13%) carried a complex karyotypes. ECOG PS was 0-1 in 66 pts (93%). At the time of the first immunotherapy, pts had received a median of 2 previous lines of treatment (1-8). All Ph- pts received intensive chemotherapy front-line; Ph+ pts received TKIs and steroids in 13 cases and intensive chemotherapy plus TKIs in 3 cases. Blina was the first salvage treatment (Blino/InO sequence) in 57 pts (80%) and InO (InO/Blina sequence) in 14 (20%). Twenty-seven pts (38%) had underwent a previous allogeneic hematopoietic stem cell transplantation (HSCT). At the start of Blina as first immunotherapy, the median bone marrow (BM) blast count was 40% (0-100%); at the start of InO as first immunotherapy, the median BM blast count was 64% (2-90%). An extramedullary involvement was present in 5 patients (9%) in the Blina/InO group and in 1 patients (7%) in the InO/Blina group. During immunotherapy, the median number of lumbar punctures was 2 (0-9). A median of 2 cycles were administered for both Blina (range 1-9) and Ino (range 1-4). In the Blina/InO group, after Blina a G3/4 toxicity occurred in 15 cases (26%): non-hematologic in 12 cases (21%), neurologic in 6 (8%). Infections occurred in 17 pts (30%). In the InO/Blina group, after InO a G3/4 toxicity occurred in 3 pts (21%), with extra-hematologic toxicity in 2 cases (14%, liver toxicity 1 case). Infections occurred in 4 cases (28%). In the Blina/InO group, after Blina 36 pts (63%) achieved a complete remission (CR), with a negative minimal residual disease (MRD) in 24 (42%) pts; after InO, a CR was re-achieved in 47 pts (82.4%), with 34 (59.6%) being MRD-. In the InO/Blina group, after InO a CR was reached in 13 cases (93%), with 6 pts (42.8%) being MRD-; after Blina, a CR was re-achieved in 6 pts (42.8%), with 3 (21.4%) being MRD-. This salvage immunotherapy strategy represented a bridge to alloHSCT for 26 pts (37%). From the first immunotherapy, in the Blina/InO group, the median overall survival (OS) was 19 months and after InO 6.3 months (OS in MRD- vs MRD+, p ns). Disease free survival (DFS) after Blina was 7.4 months (11.6 vs 2.7 months in MRD- vs MRD+ pts, p .03) and after InO it was 5.4 months (MRD- vs MRD+ pts, p ns). In the InO/Blina group, the median OS was 9.4 months and after Blina 4.6 months (7.5 vs 2.8 months in MRD- vs MRD+ pts, p .02). DFS after InO was 5.1 months (MRD- vs MRD+ pts, p ns) and after Blina it was 1.5 months (8.7 vs 2.5 gg in MRD- vs MRD+ pts, p .02). OS and DFS in MRD- pts after Blina was significantly better, both in the Blina/InO and the InO/Blina groups. With a median follow-up of 16.5 months from the start of immunotherapy and 33.8 months from initial diagnosis, 24 pts (34%) are alive and 16 (22%) are alive in CR. Four patients (6%) died in CR due to veno-occlusive disease during HSCT after InO treatment. Interestingly, OS and DFS from the first immunotherapy was better in pts with a previous alloHSCT (median survival 24.2 vs 13 months, p=.0135). AlloHSCT after second immunotherapy was associated with a better OS and DFS (OS 9.8 and DFS 7.2 months vs 7.8 and 4.4 months, p ns). Our real-life study in R/R B-cell ALL pts with multiple previous lines of treatment demonstrates the feasibility and efficacy of a sequential immunotherapy strategy in terms of MRD response, DFS and OS, and as a bridge to HSCT. SM and PC: equal contributors Disclosures Papayannidis: Janssen: Honoraria; Astellas: Honoraria; AbbVie: Honoraria; Amgen: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Curti: Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Chiaretti: amgen: Consultancy; pfizer: Consultancy; novartis: Consultancy; Incyte: Consultancy. Forghieri: Jannsen: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Jazz: Honoraria. Bonifacio: Bristol Myers Squibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cerrano: Janssen: Honoraria; Insight: Honoraria; Jazz: Honoraria. Fracchiolla: Gilead: Honoraria, Speakers Bureau; Abbvie: 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, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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