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  • 1
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 4848-4848
    Abstract: Abstract 4848 Objectives: the prognosis of patients with cytogenetically normal acute myeloid leukemia (CN-AML) is highly variable and can be influenced by several clinical and biological variables. Nevertheless, some biological data may be conflicting and difficult to combine with the clinical ones. Methods: in order to propose a simple scoring system, we retrospectively analysed the clinical data of 337 patients newly diagnosed with CN-AMLs, aged less than 65 years, consecutively treated in eleven hematological Italian Centres from 1990 to 2005. Two hundred nineteen patients (65%) received a fludarabine-based induction regimen. All the other patients received a conventional induction regimen, including cytarabine, one anthracycline with or without etoposide. Univariate and multivariate analysis on event free survival and overall survival (EFS and OS) were performed. Patients addressed to allogeneic stem cell transplantation were censored at the time of transplant. Factors found to be significant in univariate analysis were tested in multivariate analysis. A numerical score was derived from the regression coefficients of each independent prognostic variable. The Prognostic Index Score (PIS) for each patient was then calculated by totalling up the score of each independent variable. Patients could thus be stratified into low-risk (score = 0–1), intermediate-risk (score = 2) and high-risk group (score grater than 3). The score obtained in this group of patients (training set) was then tested on 193 patients with newly diagnosed with CN-AMLs, aged less than 65 years, enrolled in the GIMEMA LAM99p clinical trial (validation set). Results: the clinical variables that were independent prognostic factors on EFS in the training set of patients were: age 〉 50 yrs (regression coefficient: 0.39, HR 1.5, score = 1), secondary AML (regression coefficient: 0.90, HR 2.5, score = 2) and WBC 〉 20 × 10^9/L (regression coefficient: 0.83, HR 2.3, score = 2). For what concerns the OS, the same variables showed the followings statistical data: age 〉 50 yrs (regression coefficient: 0.48, HR 1.6, score = 1), secondary AML (regression coefficient: 0.99, HR 2.7, score = 2) and WBC 〉 20 × 10^ 9/L (regression coefficient: 0.87, HR 2.4, score = 2). In the training set of patients, the median EFS was 22, 12 and 8 months in the low, intermediate and high-risk group (p 〈 0.0001). The median OS was not reached in the low-risk group and was 20 and 10 months in the intermediate and high-risk group (p 〈 0.0001). In the validation set of patients, the median EFS was 66, 16 and 3 months in the low, intermediate and high-risk group (p 〈 0.0001). The median OS was 66, 16 and 4 months in the low, intermediate and high-risk group (p 〈 0.0001). Conclusions: this simple and reproducible prognostic score may be useful for clinical-decision making in newly diagnosed patients with CN-AMLs, aged less than 65 yrs. Moreover, it can be clinically useful when the molecular prognostic markers are lacking (e.g. in emerging laboratories of some developing countries) or give contradictory results. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e23073-e23073
    Abstract: e23073 Background: Despite cancer survivorship research for patients with solid tumours is increasing, there is paucity of data for patients with hematologic malignancies. We aimed to: 1) investigate factors associated with development of fatigue in long-term APL survivors; 2) describe prevalence of other key symptoms and functional limitations by fatigue severity. Methods: The current analysis is based on 244 APL survivors with a median follow-up from diagnosis of 14.3 years, who were recruited in a large multicenter study. Fatigue was evaluated with the validated FACIT-Fatigue scale. Multivariate linear regression analysis was used to investigate factors associated with self-reported fatigue and key clinical and treatment-related variables were also considered in the analysis. Patients were also divided into two groups based on the FACIT-Fatigue median score identifying a low fatigue (LF) and a high fatigue (HF) group. Prevalence (i.e., not present, mild and moderate to severe) of key symptoms and functional limitations, measured with the EORTC QLQ-C30, were also analyzed by fatigue severity. Results: Multivariate analysis showed that a lower age at diagnosis (p = .002), absence of comorbidities (p = .001) and a greater social support (p = .004) were independently associated with lower fatigue. Patients in the HF group had a significantly higher prevalence of many symptoms, including: pain (p 〈 .001), dyspnea (p 〈 .001), insomnia (p 〈 .001), appetite loss (p = .010), nausea and vomiting (p = .026) and diarrhea (p = .002) than patients in the LF group. As an example, whilst in the HF group there were 61% of patients also reporting pain (with any level of concern), in the LF group there were only 26% of patients reporting pain. Also, HF patients reported a significantly higher prevalence of functional limitations including: physical, role, social, emotional and cognitive functioning (each with p 〈 .001). Conclusions: Our data provides novel information of factors that are independently associated with fatigue severity in long-term APL survivors. Greater fatigue is also associated with a substantial burden of other symptoms and functional limitations.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
    detail.hit.zdb_id: 604914-X
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  • 3
    In: Blood, American Society of Hematology, Vol. 134, No. 12 ( 2019-09-19), p. 935-945
    Abstract: A risk-adapted, MRD-driven transplant strategy is a feasible approach for the treatment of younger adults with AML. Pretransplant MRD positivity should not contraindicate delivery of an allogeneic stem cell transplant.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    In: Leukemia, Springer Science and Business Media LLC, Vol. 33, No. 7 ( 2019-7), p. 1598-1607
    Type of Medium: Online Resource
    ISSN: 0887-6924 , 1476-5551
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2019
    detail.hit.zdb_id: 807030-1
    detail.hit.zdb_id: 2008023-2
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  • 5
    In: Leukemia & Lymphoma, Informa UK Limited, Vol. 52, No. 12 ( 2011-12), p. 2329-2335
    Type of Medium: Online Resource
    ISSN: 1042-8194 , 1029-2403
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2011
    detail.hit.zdb_id: 2030637-4
    detail.hit.zdb_id: 1042374-6
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  • 6
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 770-770
    Abstract: Background The combination of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy regimens is currently considered the standard of care for newly diagnosed acute promyelocytic leukemia (APL) patients. This combination has greatly contributed to convert APL from a frequently fatal disease to a highly curable one. However, there is lack of data on the impact of such therapies on patients’ health-related quality of life (HRQOL). Objective The main objective of this study was thus to investigate long-term HRQOL of APL patients previously treated with ATRA plus anthracycline-based chemotherapy. The physical and mental HRQOL profile of these patients was compared with that of matched control subjects from the general population to identify specific areas most in need of attention in long-term follow-up care. A secondary objective was to outline symptoms’ burden from the patients’ perspective. Patients and Methods Data were gathered through an ongoing multicenter survivorship study that recruits APL patients previously enrolled in two large GIMEMA trials (i.e., AIDA0493 and AIDA 2000). In both trials, APL patients were treated with ATRA plus Idrarubicin (AIDA). The main inclusion criterion was having survived the initial diagnosis for more than 5 years and being in complete remission (CR). Generic HRQOL was assessed with the SF-36 that consists of 36 items covering eight generic health status/QoL domains: physical functioning (PF), role limitations due to physical health (RP), bodily pain (BP), general health perceptions (GH), vitality (VT), social functioning (SF), role limitations due to emotional problems (RE) and mental health (MH). All scales ranged between 0 and 100, with the higher scores representing better outcomes. Clinical significance was evaluated and eight points were considered to be a minimally important difference for the eight SF-36 scales. Mean SF-36 scores were compared to available national general population reference values (i.e., 1997 subjects without cancer) and all analyses were adjusted for age and gender. Symptom burden was assessed according to the M.D. Anderson Symptom Inventory (MDASI). Symptom severity was assessed for the following symptoms: fatigue, pain, sleep disturbance, drowsiness, poor appetite, shortness of breath, nausea, vomiting, dry mouth, numbness, difficulty remembering, distress and sadness. All items were rated on a numeric rating scale from 0 to 10, with the higher scores indicating a higher level of symptoms. These were categorized as “mild” (ratings between 0 and 3) and “moderate to severe” (ratings between 4 to 10). Results Analysis is based on 136 adult APL patients who agreed to participate. At study participation, the mean age of patients was 52 years (55% males and 45% females) and the median time from diagnosis was 13 years (range: 4.5-20). Age and gender adjusted comparisons between APL patients and the general population norms revealed worse outcomes for the following scales: RP (P & lt;.001) and RE (P & lt;.001). Such differences were more than six times the magnitude of a clinically meaningful difference (i.e., at least 8 points), respectively for the physical (Δ=51 points) and the emotional scales (Δ=49 points) of the SF-36. Analysis within our patient cohort revealed that older APL patients (i.e., those aged more than 52 years) had a statically significant lower physical functioning (P & lt;.001) and higher pain severity (P=.0448) than younger ones. Investigation of the HRQOL profile of patients by trial participation (i.e., AIDA 0493 vs. AIDA 2000) or time since diagnosis (cut-off median time of 13 years) revealed no difference in all scales of the SF-36. Fatigue was the most burdensome symptom being reported as moderate to severe in 35% of patients. Other frequently reported moderate to severe symptoms were: difficulty in remembering (30%), sadness and distress (29%). Conclusions Although ATRA plus anthracycline-based chemotherapy regimens have greatly increased cure rates in APL, the HRQOL of these patients is heavily affected by the consequences of the disease and treatment, that persists many years after diagnosis and treatment. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 6 ( 2017-02-20), p. 605-612
    Abstract: The initial results of the APL0406 trial showed that the combination of all- trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and Methods The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 10 9 /L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively ( P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively ( P 〈 .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
    detail.hit.zdb_id: 2005181-5
    detail.hit.zdb_id: 604914-X
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  • 8
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 392-392
    Abstract: Following the identification, in collaboration with the Spanish PETHEMA group, of distinct prognostic categories among APL patients receiving AIDA-like therapies (Sanz et al. Blood 2000) the Italian GIMEMA group designed a protocol for newly diagnosed APL (AIDA-2000) in which the intensity of post-remission treatment was adapted to the relapse risk. A total of 298 PML/RARa-positive patients with median age 40 yrs (range 1–60) were enrolled during the period January 2000 – February 2003 from 64 Italian institutions. After the standard AIDA-0493 induction (Mandelli et al, Blood 1997), patients with low- and intermediate-risk received 3 anthracycline-based consolidation courses with idarubicin, mitoxantrone, and idarubicin as in the PETHEMA LPA-96 (Sanz et al. Blood 1999), whereas patients with high-risk disease (WBC 〉 10 x 109/L) received the same 3 anthracycline courses with the addition of cytarabine, etoposide and cytarabine plus 6-thioguanine during the first, second and third course, respectively, as in the original AIDA. In addition, distinct from those in the AIDA-0493, all patients enrolled in the AIDA-2000 received concomitant ATRA 45 mg/m2 for 15 d during each consolidation course. The results of the AIDA-2000 series were compared to those obtained in 346 consecutive patients (median age 36 yrs, range 1–60) enrolled in the AIDA-0493 study during the period May 1997 – May 2000. All patients in either studies who tested PCR-negative post-consolidation received ATRA maintenance for a total of two years. After induction, 323/338 (96%) and 276/294 (94%) evaluable patients achieved CR in the AIDA-0493 and AIDA-2000, respectively (P=0.34). Molecular remission was obtained after consolidation in 291/296 (98%) and 235/238 (99%) patients (P=0.69). With a median follow-up of 4.5 and 2.0 yrs in the two studies, the DFS at 2.0 yrs for patients in the AIDA-0493 and AIDA-2000 was 84% and 90%, respectively (P=0.09), whereas the CIR rate at 2.0 yrs was 14% and 5%, respectively (P=0.04). Five and 9 patients died in CR in the two series and were equally distributed among risk groups. By comparing separately the distinct risk groups in the AIDA-0493 and AIDA-2000, there was no significant difference in the CIR rate for low- (3% vs. 2%) and intermediate-risk (11% vs. 9%) groups, while a significantly higher CIR was observed in the AIDA-0493 for high-risk (29% vs. 2%, P=0.0004). In line with recent PETHEMA results, our data confirm that anthracycline-based consolidation is equally effective as cytarabine-containing regimens for patients with low- and intermediate-risk and suggest that a risk-adapted strategy including ATRA for consolidation provides an outcome improvement in newly diagnosed APL. In addition, our results suggest a benefit in terms of relapse rate reduction using cytarabine coupled to anthracyclines and ATRA during consolidation in the high-risk group.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 9
    In: Blood, American Society of Hematology, Vol. 109, No. 10 ( 2007-05-15), p. 4432-4440
    Abstract: Alteration of lineage-specific transcriptional programs for hematopoiesis causes differentiation block and promotes leukemia development. Here, we show that AML1/ETO, the most common translocation fusion product in acute myeloid leukemia (AML), counteracts the activity of retinoic acid (RA), a transcriptional regulator of myelopoiesis. AML1/ETO participates in a protein complex with the RA receptor alpha (RARα) at RA regulatory regions on RARβ2, which is a key RA target gene mediating RA activity/resistance in cells. At these sites, AML1/ETO recruits histone deacetylase, DNA methyltransferase, and DNA-methyl-CpG binding activities that promote a repressed chromatin conformation. The link among AML1/ETO, heterochromatic RARβ2 repression, RA resistance, and myeloid differentiation block is indicated by the ability of either siRNA-AML1/ETO or the DNA methylation inhibitor 5-azacytidine to revert these epigenetic alterations and to restore RA differentiation response in AML1/ETO blasts. Finally, RARβ2 is commonly silenced by hypermethylation in primary AML blasts but not in normal hematopoietic precursors, thus suggesting a role for the epigenetic repression of the RA signaling pathway in myeloid leukemogenesis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2007
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2004-2004
    Abstract: Background. Similar probabilities of survival have been reported for patients transplanted from Matched Unrelated Donor (MUD), Umbilical Cord Blood (UCB) or Haploidentical (Haplo) donors as alternative hematopoietic stem cell sources. However, few studies have compared these results with those obtained in patients transplanted from HLA Id-siblings (Id-sib). Moreover, all reported studies are retrospective and the criteria of donor selection were not predefined. We report the intention to treat (ITT) analysis results on 238 patients with high-risk acute myeloid leukemia (AML) prospectively transplanted according to the policy of the Rome Transplant Network (RTN), a metropolitan transplant program established in Rome in 2006. Patients and Methods. For AML patients eligible to an allogeneic transplant, the RTN policy consists of an algorithm of donor choice based on a hierarchy according to the following criteria: 1) HLA identical sibling; 2) MUD ≥8/10 HLA 3) UCB as single unit selected on the base of cell dose and number of HLA disparities (0-1/6 HLA: TNC ≥2.5x107/kg and CD34 ≥1x105/kg; 2/6 HLA: TNC ≥3.5x107/kg and CD34 ≥2x105/kg); 4) G-CSF primed, unmanipulated bone marrow Haplo donor. Myeloablative (MAC) or reduced intensity (RIC) TBF (Tiothepa, Busulfan, Fludarabine) conditioning regimen was identical for all patients, GVHD prophylaxis was uniform for each categories. of transplant Results. From January 2006 to December 2014, 238(89%) out of 303 adult patients candidates to an allogeneic transplant for high-risk AML were considered eligible. Overall, a donor was available for 205 (86%) of 238 eligible patients. At time of the analysis, 17 of these 205 patients (8%) had lost the transplant eligibility and 4 (2%) were still scheduled for transplant, therefore 184/205 (90%) patients with an available donor were finally transplanted from Id-sib (n=76), MUD (n=38), UCB (n=17) or Haplo (n=53) donors. The 8-yrs overall survival (OS) of the 238 eligible patients from time of HLA typing and of the 184 transplanted patients from time of the graft was 40±4%and 43±4%, respectively. By excluding the low number of UCB recipients (n=17), the OS was particularly dismal for the 34 patients transplanted in advanced disease phase (7±4% at 4 yrs), whereas for the 132 patients transplanted in early (CR1+ CR2) phase the 8-yr OS was 56±5%: 58±7% for 61 HLA Id-sib, 50±8% for 40 Haplo and 63±10% for 27 MUD recipients (P=NS). The OS of patients transplanted in early phase was 63±5% for 97 patients receiving MAC and 33±9% for RIC recipients. For these 97 patients, the survival by type of donor was 62±10% either for 47 Id-sib or 28 Haplo and 70±10% for 22 MUD recipients (P=NS). The results were analyzed by various donor/recipient (D/R) combinations such as age, sex and CMV status. The median donor age was 39 years (range, 18-70) and the median patient age was 43 years (range, 16-59): the 8-yr OS of patients (n=30) with younger D/R combination (D 〈 39y-R 〈 43y) was79±9%, significantly higher than 55±7% observed for the other D/R combinations (P=0.04). The 4 D/R sex combinations were homogeneously distributed among Id-sib, MUD and Haplo recipients: for 51 sex mismatched (DM/RF; DF/RM) patients the 8-yr OS was 73±7%, significantly higher than the 53±8% rate observed for 46 sex matched patients (P=0.03). Finally, the 8-yr OS by D/R CMV status was 68±6% for 74 D/R CMV matched and 46±12% for D/R CMV mismatched patients (P=NS). In multivariate analysis, the factors influencing survival were D/R age (P=0.059), D/R sex (P=0.03) and D/R CMV status (P=0.04). The donor source (Id-sib vs MUD vs Haplo) did not affect survival (P=NS). Conclusions. RTN policy allowed donor identification in 86% of all eligible AML patients and allowed an allogeneic transplant to be carried out in 90% of them with no substantial differences in terms of long-term survival between initially eligible (ITT analysis) and definitively transplanted patients. Only the definition of a specific transplant policy and the ITT analysis allow to evaluate the real impact of a transplant program. As the probability of survival is not substantially different comparing different donor stem cell sources, the final conclusion which can be drawn from our study is that for patients with AML undergoing an allogeneic transplant, the HLA matching is unlikely to remain the first criterion for donor identification. Other factors such as D/R age, sex and CMV status should drive the search for the best donor. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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