Associazione QOL-ONE.

Background: In myelodysplastic syndromes (MDS), thrombocytopenia is associated with mortality and treatments in this setting are scarce. We tested whether eltrombopag, a thrombopoietin receptor agonist, be effective in improving outcomes in lower-risk MDS with severe thrombocytopenia within a multicentre clinical trial (EQoL-MDS). Initial interim results of short-term efficacy and safety have been published (Oliva et al. Lancet Hem 2017) in the first 90 subjects. We present interim results of the second phase for long-term results in the initial 90 of 174 subjects. Methods: In a single-blind, randomised, controlled, phase 2 trial of adult patients with International Prognostic Scoring System (IPSS) low- or intermediate-1-risk MDS and severe thrombocytopenia. Adult patients with a stable platelet (PLT) count <30 Gi/L are randomized (2:1) to receive eltrombopag (50 mg to 300 mg) or placebo for at least 24 weeks and until disease progression. We report results of the second phase of the trial with primary endpoints duration of PLT response and long-term safety and tolerability. Amongst secondary endpoints, we present changes in quality of life (QoL), overall survival (OS) and leukemia-free survival (LFS). Results: The first 90 subjects were enrolled between 2011 and 2016. Characteristics of patients have been previously published (Lancet Hem 2017). PLT responses occurred in 28 (47.5%) of 59 patients in the eltrombopag group versus 1 (3.2%) of 31 patients in the placebo group (odds ratio 27.1 [95% CI 3.5-211.9], p=0.002) in median time 14 days (95% CI 7-40 days). Severe bleeding (WHO bleeding score ≥2) occurred in 19 patients, with a significantly higher incidence in the placebo (11 [35.3%] of 31 patients) than in the eltrombopag arm (8 [13.6%] of 59 patients; p=0.015). Sixty-eight grade 3-4 adverse events occurred in 30 of 59 (50.8%) eltrombopag patients versus 10 events in 6 of 31 placebo cases (19.4%;χ2=8,4, p=0.004, stopping rule not reached). The outcomes acute myeloid leukemia (AML) evolution, progression and death occurred in 5 (8.5%), 4 (6.8%), and 5 (8.5%), respectively of 59 eltrombopag cases versus 2 (6.5%), 3 (9.7%), 2 (6.5%), respectively of 31 placebo cases (P ranging from 0.69 to 1.00). Median LFS, combined outcome (AML, disease progression and death) and OS were not reached in the whole group. Differences in LFS, combined outcome and OS at 2 and 5 years by study arms were adjusted for baseline bone marrow blasts since the proportion of patients with >2% blasts (i.e. the median value of the whole study cohort) tended to be higher (P=0.06) in Eltrombopag (59.3%) than in placebo treated (38.7%) patients and resulted to be a strong predictor of study outcomes at both 2 and 5 years (P<0.002). The between-arm difference in LFS, combined outcome and OS at 2 and 5 years ranged from 0.33 to 0.99 (Fig.1 A-C). QOL-E and EORTC QLQ-C30 scores at baseline have been previously reported (Lancet Hem 2017). Within-arm longitudinal analyses showed that subjects on placebo experienced a significant worsening in QOL-E sexual domain (P=0.025) whereas subjects in the eltrombopag arm had a significant improvement in QOL-E MDS specific (P<0.001) and total scales (P=0.047) and a trend of improvement in QOL-E physical and social scores (both P=0.054). Between-arm comparison revealed that longitudinal changes in QOL-E MDS specific domain significantly differed between the two study arms in favour of eltrombopag (P=0.005). Finally, QOL-E functional (P=0.026), social (P<0.001), fatigue (P=0.01), MDS specific (P<0.001), general (P=0.001), treatment outcome index (P<0.001) and total scale (P<0.001) significantly improved with increasing PLT counts. Conclusion. Eltrombopag is well-tolerated in patients with lower-risk MDS and severe thrombocytopenia and is clinically effective in raising PLT count and reducing bleeding events. QoL improves with response to treatment. The assessment of long-term safety and efficacy of eltrombopag and its effect on survival (phase 2 part of study) is still ongoing. Disclosures Oliva: Novartis: Consultancy, Speakers Bureau; Apellis: Consultancy; Celgene Corporation: Consultancy, Honoraria, Speakers Bureau. Alati:Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Giai:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Balleari:Celgene: Membership on an entity's Board of Directors or advisory committees. Ferrero:Novartis: Honoraria. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Fenaux:Aprea: Research Funding; Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding. Palumbo:Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Teva: Honoraria; Hospira: Honoraria. Liberati:Novartis: Other: Clinical trial support; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Roche: Other: Clinical trial support; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Clinical trial support; Celgene: Honoraria, Other: Clinical trial support; Bristol-Myers Squibb: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy. Molteni:Celgene: Membership on an entity's Board of Directors or advisory committees. Buccisano:Astellas: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bocchia:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Candoni:Merck SD: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Celgene: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Martino:Bristol myers squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Latagliata:Janssen: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. OffLabel Disclosure: Eltrombopag is indicated for: 1. the treatment of patients aged 1 year and above with primary immunethrombocytopenia (ITP) lasting 6 months or longer from diagnosis and who are refractory to other treatments; 2. in adult patients with chronic hepatitis C virus (HCV) infection for the treatment of thrombocytopenia, where the degree of thrombocytopenia is the main factor preventing the initiation or limiting the ability to maintain optimal interferon-based therapy; 3. in adult patients with acquired severe aplastic anaemia who were either refractory to prior immunosuppressive therapy or heavily pretreated and are unsuitable for hematopoietic stem cell transplantation

Aims: In elderly patients with acute myeloid leukemia (AML), complete remission (CR) rate following intensive chemotherapy is approximately 45%, considerably lower than in younger patients, with a shorter duration of remission and high treatment-related mortality (30-50%). Median survival is about 12 months. Intensive chemotherapy is indicated in a small proportion of "fit" elderly patients. In a phase III, prospective, randomized, open-label, multicenter trial designed to assess the efficacy of post-remission treatment with 5-Azacitidine versus best supportive care (BSC) in patients > 60 years of age with AML in CR after conventional induction ("3+7") and consolidation chemotherapy, quality of life (QoL) was assessed from diagnosis. We present interim results of changes of QoL. Methods: Patients with newly diagnosed AML with > 30% myeloid marrow blasts, either "de novo" or evolving from myelodysplastic syndrome without contraindications for intensive chemotherapy and with an ECOG performance status < 3 are included. Induction chemotherapy consists of two courses of "3+7": Daunorubicin 40 mg/m2 daily days 1-3 and cytarabine 100 mg/m2 daily continuous IV infusion days 1-7. Patients in CR receive consolidation (cytarabine 800 mg/m2 3 hour infusion bid days 1-3) and are randomized 1:1 to receive BSC or 5-Azacitidine maintenance therapy up to 4 years and six months until AML recurrence. QoL assessment was performed using the EORTC QLQ-C30 and the QOL-E v.3 questionaires. Results: QoL results assessed at 3 time points are reported: 1) baseline; 2) at hematological recovery immediately after the first "3+7" course; and 3) after consolidation at randomization. Ninety-nine patients (male/female 50/49) of median age 70 (IQR 65-74) years have been enrolled. At diagnosis, mean hemoglobin was 9.2 (SD ± 2.4) g/dL, leukocytes were 7.9 (2.3-29.6)/µL, platelet count was 54 (IQR 29-85) Gi/L and bone marrow blasts were 70 (IQR 50-85)%. Seventy-five patients had "de novo" AML. Twenty-three patients had comorbidities. Forty-three patients had an ECOG PS 1 and 28 had ECOG PS 2. Baseline median QOL-E scores were poor (≤60) in all dimensions, except for fatigue (76, IQR 52-85). EORTC QLQ-C30 confirmed that fatigue was not prevalent at diagnosis (median 33, IQR 22-56). Median baseline EORTC QLQ-C30 scores were good in all domains except for global health status (GHS, median 50, IQR 33-67). Gender, comorbidities, bone marrow blasts and secondary AML were not related to QoL. Baseline Hb levels correlated with QOL-E functional (r=0.0216, p=0.14), fatigue (r=0.256, p=0.002) and disease-specific (r=0.247, p=0.010) scores and with EORTC QLQ-C30 GHS (r=0.270, p=0.001), physical (r=0.304, p<0.0001), role (r=0.281, p=0.001), cognitive (r=0.262, p=0.003), social (r=0.229, p=0.010) functions and fatigue (r=-0.280, p=0.001), dyspnea (r=-0.287, p=0.001) and appetite loss (r=0.244, p=0.007). Age correlated with QOL-E disease specific scores (r=0.242, p=0.012). There were no changes in QOL-E scores following 1st "3+7". However, the EORTC QLQ-C30 detected deterioration in physical function from median 80, IQR 60-93, to 67, IQR 52-87 (p=0.008), in role function from median 83, IQR 67-100, to 67, IQR 33-83 (p=0.023) and in GHS from median 50, IQR 33-69, to 67, IQR 50-75 (p=0.002) and improvement in dyspnea (p=0.023). Forty patients obtained a CR. Interestingly, baseline role function was better (median 83, IQR 67-100) in cases obtaining a CR than in resistant patients (median 67, IQR 33-83, p=0.007). Patients obtaining CR experienced improvements after consolidation in median QOL-E physical scores from 56, IQR 41-72 to 63, IQR 50-84 (p=0.033), disease-specific domain scores from 59, IQR 48-67 to 74, IQR 67-85 (p=0.003) and treatment-outcome index scores from 55, IQR 32-77, to 79, IQR 41-86 (p=0.026). Median EORTC QLQ-C30 emotional function improved after consolidation therapy from 83, IQR 67-92, to 92, IQR 77-100 (p=0.015) as well as GHS from median 50, IQR 33-65 to 67, IQR 58-83 (p=0.002). Dyspnea and insomnia regressed while financial problems increased. Conclusions: Elderly patients with AML at diagnosis identified as fit for chemotherapy generally do not present fatigue, though health status is poor and is mainly correlated with Hb levels. Role function may predict response to induction chemotherapy. Patients obtaining CR perceive improvements in global health, including physical and emotional QoL and symptoms. Disclosures Oliva: Celgene: Other: Advisory Board, Speakers Bureau; Amgen: Consultancy; Novartis: Speakers Bureau.

Metastatic disease of the bone is a rare complication of chronic lymphocytic leukemia (CLL), it may be result from richter's transformation or metastatic from non lymphoid malignancies. CLL is the most common form of adult leukemia, with the median age of 70 years at diagnosis [Siegel et al. 2013]. The diagnosis is established by blood counts, blood smears, and immunophenotyping of circulating B-lymphocytes.The result is the increased number of lymphocytes in the peripheral blood, leukocytosis with absolute lymphocytosis, the increase of the lymphnodes, the increase in size of the spleen. The diagnosis of chronic lymphocytic leukemia B requires the presence of Clonal B cells in the peripheral blood at or above 5,000 / ul for at least 3 months. Typing immunophenotypical pathological lymphocytes are positive for surface antigens CD5, CD19, CD23, weakly positive for CD20 and CD22, generally negative FMC7 and CD79b; also expressing surface immunoglobulins. The Rai and Binet staging systems, which are established by physical examination and blood counts, have been recognized as standards for deciding whether to begin treatment. Patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. For fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab represents the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab, rituximab, ofatumumab) plus a milder chemotherapy (Chlorambucil) may be applied. At relapse, if the treatment-free interval exceeds two to three years, the initial treatment may be repeated, if the disease relapses earlier, drugs such as bendamustine (plus rituximab), alemtuzumab, lenalidomide, ofatumumab, ibrutinib, or idelalisib, must be choosen. Patients with a del(17p) or TP53 mutation can be treated with ibrutinib or a combination of idelalisib and rituximab. in relapsing patients with TP53 mutations or del(17p) or patients that are refractory to repeated chemoimmunotherapies, an allogeneic SCT may be considered [Hallek M 2015]. In this article we show a case of a 66-year-old man with CLL and a bone localization. In 2011 diagnosis of CLL, Rai Stage 0, Binet Stage A. Principal characteristics at diagnosis: HB 13.2 g /dl, White Blood Cells 15.800 / mm3, lymphocytes 61%, neutrophils 32%, monocytes 4%, platelets 141.000/mm3; normal hepatic end renal function; flowcytometric immunophenotyping of the peripheral blood revealed B-cell CLL; prognostic factors: CD38 negative, ZAP70 positive, rearrangement of the immunoglobulins mutated; FISH: negative; CT chest / abdomen / pelvis: presence of multiple aorto-pulmonary and axillary adenopathies (max diameter of 2 centimeters); bone marrow biopsy: infiltration of CLL equal to 60% of global cellularity. The patient was only observed until January 2015, when he was hospitalized due to acute anemia, requiring supportive therapy, and right foot pain . So it was decided to re-evaluate the whole disease in order to decide whether to start chemotherapy. The disease was staged again with instrumental and laboratory tests: presence of renal insufficiency, egd and colonoscopy negative, Coombs' test negative, bone marrow biopsy confirmed the diagnosis of chronic lymphocytic with bone marrow infiltration of 90%, abdomen ultrasound showed only moderate splenomegaly. On February, persistence of right foot pain and appearance of swelling, assessed by the orthopedic as a suspected algic and dystrophic syndrome. So he suggested to perform scintigraphy which revealed: pronounced inflammatory osteometabolic reaction of the right tibia/fibula/ankle third distal which could be referred, in the first evaluation, to algic and dystrophic syndrome. However, a local biopsy was performed: localization of chronic lymphocytic leukemia. On March 2015 a total body TC showed 2 nodular calcifications in the right lung lobe, multiple right paratracheal, barety space, aortopulmonary and axillary adenopathies. Prostate size increased. In order to study carefully the liver and prostate lesions, an ultrasound abdomen was performed that documented only enlarged spleen, normal size liver, free of focal disease, increased prostate due to symmetric bilobate hypertrophy . After the second cycle of chemotherapy, prolonged thrombocytopenia, so he continues only with a radiotherapy program. Disclosures No relevant conflicts of interest to declare.

Chronic lymphocytic leukemia (CLL) is an indolent lymphoproliferative disorder and is manifested by progressive accumulation of B cells in the blood, bone marrow and lymphatic tissues. Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of all the stages of myeloid development in the peripheral blood, and it is believed to be driven by the aberrant protein tyrosine kinase, a product of the mutant BCR-ABL1 gene.Multiple Myeloma (MM) is characterized by the accumulation of clonal plasmcells in the bone marrow with skeletal lesions, anemia, hypercalcemia and renal failure. Our patient is a 78 year-old man. In 2014 diagnosis of CLL and monoclonal gammopathy of undetermined significance (MGUS).At diagnosis: HB 13.5 g/dl; normal renal function;calcium 8.7 mg/dl;IgG 1678 mg/dl,serum immunoelectrophoresis: IgG kappa, Bence Jones kappa; total protein 7.5 g/dl, beta1 6,5%, beta2 24,1%;peripheral blood immunophenotyping showed CLL, FISH:negative;Cariotype: 46, XY; RX skeleton: positive for osteolytic lesions, total body TC scan: adenopathies of 18 mm and 15 mm at bilateral axillary level, norma spleen, adenopathy of 22 cm in the left obturator iliac region; presence of left hip prosthesis; bone marrow biopsy: localization by low-grade plasmacytoma.No CLL.The patient was only observed until April 2015, when there was a presence of myelocytes and metamyelocytes in peripheral blood and an increased spleen (18 cm). So he performed : bone marrow aspirate: diagnosis of CML (Sokal Score: 1,34 H; Eutos Score: 60 L, Hasford Score 1488,5);bone marrow biopsy: suggestive for a myeloproliferative disease (CML), MGUS with a modest lymphoid B component,BCR-ABL: 60;FISH: pathological presence of double fusion signal of the ABL1 and BCR loci in 209 of 271 interphase nuclei examined (77%).The patient started therapy with Imatinib, 400mg/die until July 2015, on the basis of the good response to treatment and the progressive increase of the M component that confirmed the progression to MM: Hb 9.1 g/dL, creatinine 1,1 mg/dl;calcium 10,5 mg/dl;total protein: 8,6 g/dl, gamma 48.02% (CM 4 gr); IgG 3536 mg/dl, cariotype: male with t (9; 22) and Philadelphia chromosome (25%);BCR-ABL: 14,32; bone marrow aspirate: plasmacells 15%;bone marrow biopsy: intermediate-interstitial plasmacytoma, CLL / lymphoma; RMN whole body: hyperintensity at the level of the seventh right rib; PET: osteolytic lesions of the side arch tenth right rib, right iliac bone, left iliac region, right tibia third diaphyseal.RX right hemithorax: osteolytic area at the level of the seventh right rib. So the patient started treatment with Bortezomib, Desamethasone, Alkeran (total 7 cycles).On March 2016, he performed a radiography that showed many osteolytic areas of 45 mm on third distal femur, third proximal and intermediate tibia, third proximal and third distal of fibula.A second PET documented a further MM progression due to new bone localizations and a left tibia biopsy showed localization disease. Radiotherapy colleagues have ruled out the usefulness of a radiation therapy program in consideration of the cerebral damage risk. On June 2016 the patient started a treatment with Lenalidomide for 15 days, interspersed by Glivec, maintaining the disease stable. In September 2017 he developed diplopia and with a nasal surgery, only inflammatory tissue was exported. A revision of the material confirmed plasmacytoma localization. In the same period appearance of a right gluteus sore treated initially with surgical dressing.As blood tests revealed increase of paraprotein levels, bone marrow biopsy resulted negative to myeloma and lymphoma diseases, instead a gluteal skin biopsy revealed plasmacytoma. It was decided to treat cerebral localization due to diplopia and peripherical paralysis. Radiotherapy was started on April 2018 (18 sessions). Bone marrow aspirate test showed plasmacells 15%, BCR-ABL dosage: 213,87, M component increase(5gr), IgG 4440 mg/dl, creatinine and serum calcium: normal. Due to disease progression, a rescue chemotherapy was started according to PAD protocol. After 4 cycles, a bone marrow aspirate documented the presence of plasmacells equal to 80%.The cytogenetic study confirmed the presence of a complex karyotype. So the patient started therapy with Daratumumab, Lenalidomide and Desamethasone which is currently ongoing with an excellent hematological and clinical response Disclosures Ciolli: Janssen: Honoraria; Abbvie: Research Funding.