ALBERT

Description: Background Anemia is a common symptom in patients with Myelodysplastic Syndromes (MDS) and although erythropoietic agents are often active, it is frequently treated with red blood cell (RBC) transfusions. A substantial proportion of patients might also eventually become transfusion-dependent and, Iron-chelating therapies might be important to minimize complications of iron overload. Objectives To investigate the impact of deferasirox therapy on health-related quality of life (HRQOL) of lower risk transfusion-dependent MDS patients over a one year period. Secondary objectives were to investigate relationships between HRQOL and ferritin levels and to explore the prognostic value of baseline HRQOL on the probability of achieving transfusion independence. Patients and Methods This was a prospective study whose clinical findings (i.e., primary endpoint was safety and tolerability) were previously reported. HRQOL was a secondary endpoint of the study and we herein report, for the first time, HRQOL prospective findings. Eligible patients included: MDS patients 18 years or older, International Prognostic Scoring System (IPSS) low or intermediate-1 risk and diagnosed with transfusional siderosis following a minimum of 20 blood transfusions. Patients received daily oral deferasirox at a dose between 10 and 30 mg/kg of body weight for a period of 1 year. HRQOL was assessed with the EORTC QLQ-C30. HRQOL at baseline and at 3, 6, 9 and 12 months after treatment start. The EORTC QLQ-C30 consists of 30 items and includes five functional scales (physical, role, emotional, social, and cognitive), three symptom (fatigue, nausea and vomiting and pain) and a global health status/QOL scale and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). The mean trend of HRQOL over time was estimated via a linear mixed model with a one-step autoregressive covariance structure. Such covariance structure provided the best model fit among those investigated. Results Overall, 159 patients were screened at 37 centers. The median duration of disease at enrollment was 32 months and median number of units of packed RBC received was 37. Seven patients did not start treatment at all and thus there were 152 expected HRQOL forms at baseline assessment. Out of these, 146 patients returned the questionnaire yielding a baseline compliance of 96%. No statistically significant differences over time were found for any scale of the EORTC QLQ-C30. Figure 1 depicts mean scores over time for selected scales of: fatigue, physical functioning, pain and global HRQOL. No HRQOL differences were found between patients with serum ferritin levels lower or higher than 2000 μg/L (pretreatment median value) at baseline. Also, the possible impact of ferritin level on HRQoL over time was estimated via a linear mixed model with a one-step autoregressive covariance structure. Coefficients and p values are reported in table 1. The prognostic impact of baseline HRQOL on the probability of achieving transfusion independence (i.e., defined as freedom from transfusion for 3 consecutive months) was investigated. Higher severity of pain (P=0.007) was associated with a greater likelihood of achieving transfusion independence. Multivariate analysis, controlling for age, IPSS risk score, time from diagnosis, number of previous blood transfusions and baseline ferritin level confirmed the independent value of pain (P=0.003). Conclusion Current findings suggest that Deferasirox therapy does not decrease HRQOL in lower risk transfusion-dependent MDS patients. Patients with higher baseline pain severity seems more likely to achieve transfusion independence and further analysis is needed to understand underlying reasons. Disclosures: No relevant conflicts of interest to declare.

Description: 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 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

Description: 5-azacytidine (AZA) significantly prolonged overall survival in higher-risk patients with myelodysplastic syndromes (MDS) in a large, international, randomized, phase III trial (AZA-001). However, data about efficacy and safety of AZA in lower risk MDS are less consistent and only few small studies have addressed this topic. Among a total of 246 MDS treated with AZA in 31 different Italian Institutions since 2005 within to a national patient named program, we evaluated 82 patients scored as low/int-1 IPSS risk MDS. Median age was 68 years (range 34–85), male/female ratio 50/32. According to WHO classification, there were 21 RA/RARS, 4 5q-syndromes, 20 RCMD, 24 RAEB-1, 5 RAEB-2, 4 CMMoL, and 4 MDS unclassified. Median time from diagnosis was 27 months (range 1–132). Sixty-eight patients (82.9%) were transfusion-dependent, sixty (74%) had received a prior treatment, mostly with erythropoiesis stimulating agents. AZA was administered as single drug in 61 patients (74.4%), while in the remaining subjects it was variously combined with growth factors, valproic acid or other agents. Forty-eight patients (58.5%) received a “standard” AZA dose of 75 mg/sqm/d s.c., thirty-four (41.5%) a fixed dose of 100 mg/d s.c. Single cycle treatment duration was 7 days in 45 patients (54.9%), 〈 7 days in 32 patients (39%), 〉 7 days in 3 patients (3.7%), unknown in 2 patients (2.4%). The median number of monthly cycles was 6 (range 1–21), and 63 patients (76.8%) completed at least 4 cycles. The most relevant toxicities observed (grade 3–4) were represented by myelosuppression (22%) and infections (6%). According to 2006-updated IWG criteria, overall response rate was 39% (47.5% in patients who had completed at least 4 cycles). In particular, complete response, partial response and hematological improvement occurred in 12.2%, 8.5% and 18.3% of patients (15.8%, 11.1% and 20.6% in those who were treated with at least 4 cycles), respectively. Stable or progressive disease was observed in 29.3%/25.6% and 30.2%/22.2% of patients receiving less than or at least 4 cycles, respectively. Response duration ranged from 1 to +21 months. There were no significant differences in response rate according to dose and schedule employed, although a slight trend in favour of 75 mg/sqm vs 100 mg fixed dose was seen (45.8% vs 29.4%, respectively). There was also no difference in the percentages of response according to age, previous treatment and transfusion dependence. Overall survival at 2 years was 62%. A survival benefit emerged for responding patients, compared to non responders (82% vs 57%) (p=0.015). A favourable trend was also observed for transfusion-independent patients, while age, pre-treatment and AZA dose did not influence survival. These data indicate that AZA may be safe and effective for a subset of patients with low/int-1 IPSS risk MDS, resistant or not suitable for alternative treatments. The efficacy may improve if at least 4 cycles are administered.

Description: Background: Despite the popularity of splenectomy has decreased dramatically in the past few years, the surgical approach remains the best therapy for patients with refractory Immune Thrombocytopenic Purpura (ITP) in terms of high and durable rate of response (Vesely et al, Ann Intern Med2004; 140: 112). The recent introduction of anti-CD20 antibodies and thrombopoietins of second generation such as AMG 531 and Eltrombopag may have a relevant role (Kuter et al, Lancet2008; 371: 362) but their long-term safety and efficacy have not been still established. In parallel with new drugs, there has been an evolution in the surgery of splenectomy as well (Dolan et al, Am J Hematol2008; 83: 93). Actually, the laparoscopic surgery is considered the standard approach and the ITP represents the most common indication in 50–80% of all the laparoscopic splenectomies. Methods: The aim of this study is to evaluate the long-term complete and partial haematological response (CR + PR), as well as the short and long-term complications, of 40 patients (30 females and 10 males; median age: 38 years - range 6–71) with unresponsive ITP after one or more medical approaches and underwent laparoscopic splenectomy at our Institution from 1999 through 2006. The 40 patients accounted for 22.2% of 181 patients diagnosed in those years. An abdominal CT scan to evaluate the presence of accessory spleens was performed in all cases. All patients received meningococcal, pneumococcal and haemophilus influenzae vaccine one week before splenectomy. For 4 or 5 days before splenectomy the patients were treated with high doses of intravenous Immunoglobulins. Anti-thrombotic prophylaxis was performed with low molecular weight heparin (LMWH) for 10 days and afterwards with cardioaspirin (ASA) if the platelet count exceeded 500x10E9/L. Results: No cases required conversion to laparotomic splenectomy. An accessory spleen was found in 2 patients (5%). Immediate haematological response rate was of 100%. At date, after a median follow-up of 78 months (range 28–112 months), 36 patients (90%) remain in CR or PR with a platelet count more than 50x10E9/L and 2 patients are taking ASA. Four patients (10%) relapsed; out of which, 2 patients have a platelet count less than 10x10E9/L. Short and long-term mortality rate was 0%. Immediate postoperative complications rate was 5%: we observed 2 cases of hemoperitoneum related to a trocar’s tube and to an active bleeding, respectively, both resolved with new laparoscopic approach. The mean postoperative hospital stay was 4,5 days (range 4–8). Neither cases of bacterial sepsis in the postoperative or during the follow-up time, nor cases of splenic-portal vein thrombosis (SPVT) and no cases of neoplasms occurred. Conclusions: Our experience suggests that laparoscopic splenectomy is an excellent approach to patients with refractory ITP in terms of safety, efficacy and costs. With respect to laparotomic splenectomy, the use of laparoscopy is likely to make the splenectomy even safer and therefore suitable for a larger number of patients. Undoubtedly there is a great expectation for the new drugs (Rodeghiero et al, Am J Hematol2008; 83: 91) and we agree that only controlled comparative clinical trials (Vianelli et al, Haematologica2005; 90: 72) will be able or not to say a final word and to challenge the role of splenectomy.

Description: The role of ASCT in AML appears to be appropriate in patients with favorable cytogenetic features whereas allogeneic SCT is appropriate in those with high-risk cytogenetic features. Gemtuzumab ozogamicin (GO), a monoclonal antibody conjugated to the calicheamicin, targets the CD33+ cell surface marker that is expressed on cells in the majority of AML patients. Clinical trials currently underway are investigating the role of GO in consolidation therapy. We hypothesized that GO could have beneficial effects as maintenance therapy after hematopoietic SCT in high-risk patients. Here we report data on 4 AML patients in CR who received 4 doses of GO as maintenance therapy following ASCT. Our approach differs from previous reports in the literature in that, instead of using GO to induce a first remission or re-induce a second remission after relapse, we administered GO to patients while they remained in remission, two months after undergoing ASCT. Patient #1 was a 64 year-old male with 88% CD33 expression at diagnosis. This patient had previously undergone an ASCT using a conditioning regimen of Bu+Cy. He was in second CR following an induction regimen of 2 cycles of fludarabine + cytarabine + idarubicin. Patient #2 was female, aged 67 years and had 90% CD33 expression at diagnosis. She was in first CR following an induction regimen of 2 cycles of etoposide + cytarabine + idarubicin. Patient #3 was a 69-year old male with 95% CD33 expression at diagnosis. He was in first CR following an induction regimen of 2 cycles of fludarabine + cytarabine. Patient #4 was a 59 year-old male with 93% CD33 expression. He was in first CR after a second line treatment with mitoxantrone, cytarabine and etoposide. Histocompatible donors were not available for any of the patients. Three months after attaining CR, all 4 patients received a myeloablative conditioning regimen with B(A)VC, Bu+Cy, Bu+Cy and TBI+Melphalan, respectively, and underwent ASCT. Two months after the ASCT procedure, patients initiated treatment with GO: GO was administered alone for 4 doses with 28 days between doses (two patients received 6 mg/mq for the two first doses and 3 mg/mq for the two last doses; two patients received 3 mg/mq for four doses). All four patients remain alive and in CR at +17, +13, +11and + 5 months. Overall survival at the time of reporting is +35, +15, +13 and +8 months in patients 1, 2, 3 and 4, respectively. There were no cases of grade 3 or 4 liver toxicity and bleeding was not observed in any of the patients. Thrombocytopenia (50,000–100,000 cells/μL) occurred in all four patients and neutropenia (500–1000 cells/μL) in two patients. In conclusion in our small series GO demonstrated good efficacy when administered in fractionated doses as maintenance therapy after ASCT in patients with CD33+ AML in first or second CR. GO showed an acceptable tolerability profile, with no severe hepatotoxicity and no bleeding. Thrombocytopenia occurred in all three patients and in all cases there was a rapid platelet recovery. A GO dose of 3 mg/m2 appeared to be better tolerated than the higher dose (6 mg/m2) and will be used in future studies. If confirmed in a study involving a larger number of patients, our results could support a new therapeutic role for GO, namely as a maintenance therapy for patients in CR following hematopoietic SCT.

Description: ASCO guidelines recommend the use of granulocyte-colony stimulating factors (G-CSF) as adjuvant agents after autologous peripheral blood stem cell transplantation (PBSCT), for shortening the period of severe neutropenia and reducing the related risk of life-threatening infections. The recently available pegylated formulation of G-CSF (peg-filgrastim) could have some potential advantages in phase of recovery after PBSCT, such as self-regulation mechanisms, particularly useful when neutropenia duration is unforeseeable, possible reduction/standardization of growth factor costs and possibility of more manageable outpatient treatments. We investigated the effects of a single s.c. injection of peg-filgrastim (6 mg) on day 3 in 11 patients (8 with multiple myeloma, MM; 2 with non-Hodgkin’s lymphomas, NHL; 1 with acute myeloid leukemia, AML) planned to receive autologous PBSCT. Mean age was 55 years (range 24–65). In 7 patients PBSCT was performed as consolidation in first complete or partial remission, while 4 patients received the procedure as salvage treatment for chemo-sensitive disease. Conditioning regimens were intermediate/high dose melphalan in MM, BEAM protocol in NHL and TBI plus cyclophosphamide in AML. For comparison, we selected a group of 11 historical controls matched for age, type and status of disease, conditioning regimen, and number of CD34+ stem cells infused, who had received standard daily s.c. administration of G-CSF (300 mcg/d) from day 5 to neutrophil recovery after autologous PBSCT. No adverse events occurred in patients treated with peg-filgrastim. Bone pain was the only side effect referred by one patient. There was no difference between the two groups in terms of median time to hemoglobin recovery, days of febrile neutropenia and number of red cell or platelet transfusions received. However, the median times to neutrophil 〉 0.5 x 109/L (10 days, range 9–13 vs 12 days , range 11–14, p 〈 0.000) and platelet 〉 20 x 109/L (10 days, range 8–15 vs 13 days, range 12–20, p 〈 0.003) were significantly shorter in peg-filgrastim group. The median number of G-CSF injections in controls was 12 (range 9–20), so that the mean cost of this drug for single patient was 1,764 euros, as compared to 910 euros for patients receiving peg-filgrastim. We conclude that peg-filgrastim and G-CSF have comparable safety and efficacy profiles in patients affected by hematological malignancies who undergo autologous PBSCT. In this specific setting of patients, peg-filgrastim could be cost-effective. Whether peg-filgrastim may be also superior in reducing the periods of neutropenia and thrombocytopenia, requires to be confirmed and further investigated in larger studies.

Description: The Lymphomatous Meningitis (LM) is an uncommon event, either as an initial diagnosis and in the course (or as an outcome) of a front line treatment. In the latter cases the LM has a poor prognosis and a median survival of few months in untreated patients. Its occurrence is tightly related to the histology, the response to the therapy and the introduction of a proper prophylaxis. Currently, high doses of Methotrexate (HD-MTX) (3 g/sqm) followed by radiotherapy (WBRT: 50 Gy) represents the elective treatment. The role of the intrathecal therapy (IT-T) isn’t well defined: as a matter of facts, it doesn’t seem more effective than the systemic treatment with HD-MTX and it is burdened by a higher neurotoxicity. Furthermore, more frequent intrathecal administrations, a proper concentration and a prolonged exposition to the drugs are required. Recently, an important role both in the prophylaxis and in the therapy of LM is played by the IT-T of Cytarabine in liposomal formulation (DepoCyte): the slow release from the multivescicular lipidic particles improves the distribution in the liquor, allows a lesser number of IT-T, reduces the undesired effects due to the treatment and increases the compliance of patients. Randomized studies have shown a significant better effectiveness and a reduced toxicity of liposomal formulation treatment with respect to the traditional one. In the present work 9 cases of LM treated with systemic chemotherapy and with DepoCyte (50 mg IT every 15 days x 6 times) are shown. Male/Female ratio is 6/3; average age is 46 years (range 24–78). In all patients neurological symptoms were present; lymphomatous cells were identified in the CSF of 5 patients and Central Nervous System (CNS) localizations were detected by NMR in 7 patients. The 5 CSF-positive cases were heterogeneous, as follows: B-lineage CD10+ ALL meningeal relapse (after two marrow relapses), already undertaken to allogeneic stem cells transplantation, treated only with DepoCyte; Lymphoblastic T-Cell Lymphoma meningeal localization, with mediastinic mass, treated with DepoCyte associated to LSA2L2 Protocol and autologous stem cells tranplantation; DLBCL meningeal localization treated with DepoCyte associated to R-CHOP Protocol; LM at diagnosis in a 78 years old patient with inadequate compliance to systemic therapy, treated with DepoCyte; Mantle Cell Lymphoma meningeal (and systemic) relapse treated with DepoCyte associated to Codox-M Protocol. In patients 1) to 4) the CR was obtained and they are still alive; only the latter patient, namely, case 5), died for disease progression. The remaining 4 CSF-negative cases had been diagnosed as DLBCL (3 at diagnosis and 1 at relapse) CNS solitary localizations. In all cases L-VAMP Protocol (modified with HD-MTX) was associated to IT-T with DepoCyte. With the only exception of the relapsed patient, the remaining 3 patients had a good response to therapy and they are still alive and in CR.Overall, DepoCyte was shown to be mostly effective, well tolerated by all patients and devoid of undesired side effects. The association with various systemic chemotherapy protocols had been demonstrated to be suitable and endowed with synergic effects. Studies with higher number of patients might validate the effectiveness of DepoCyte also in those CSF-negative cases with solitary CNS localization.

Description: Abstract 923 Introduction: The increased risk of bleeding in myelodysplastic syndromes (MDS) is due to low platelet (PLT) counts and abnormalities of PLT morphology and function. Severe thrombocytopenia occurs in about 10% of low and Int-1 International Prognostic Scoring System (IPSS) risk MDS patients in whom PLT transfusions are indicated mainly in the presence of bleeding. Short therapeutic effect and the development of refractoriness to PLT transfusions motivate research in novel treatments. Eltrombopag is an oral, non peptide, non-competitive agonist of the thrombopoetin-receptor (TPOR) which interacts selectively with the TPOR transmembrane domain to initiate TPO signaling. Eltrombopag is indicated for the treatment of thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura. Its potential in increasing PLT count in lower risk MDS has not been evaluated. Study Design and Methods: We present preliminary results of a Phase II, multicentre, prospective, placebo-controlled, single blind study to evaluate the safety and efficacy of eltrombopag in low and intermediate-1 risk adult MDS patients with PLT count 200 Gi/L or adverse events. PLT response is defined as Response (R) if: 1) baseline 〉 20 Gi/L: absence of bleeding and absolute increase in PLT ≥ 30 Gi/L/mm3; 2) baseline 〈 20 Gi/L: PLT

Description: To evaluate clinical and biological features, treatments and outcome of patients(pts) with Systemic Mastocytosis(SM). A retrospective study (1995–2006) about pts with SM admitted in 14 Italian hematology divisions in tertiary cares or university hospitals. 30 cases of SM were collected(median age 62 y.o.; M/F 14/16) and classified according to the WHO criteria: Mast Cell Leukemia in 14 pts, Aggressive SM in 12 and Indolent in 3; the remaining one had SM with associated clonal non-mast cell-lineage hematologic disease. Skin was the principal extramedullary organ involved (19 pts) followed by spleen(15), liver(13), and cardiovascular system(12). Molecular biology studies were performed in 22 pts: 15 showed the c-kit point mutation D816V; in another patient a different c-kit mutation was found while in 3 pts additional gene defects and karyotype abnormalities were recognized. Treatments were heterogeneous, and the same patient could have received different therapies after failure of the previous one. Imatinib(400 mg/day) was used in 17 pts (11 as first line therapy, 5 and 1 as second and third line respectively); interferon-alpha(3×3 MU s.c. weekly) was employed in 7 patients(4 as first line therapy, 2 as second and 1 as third line); 2-CDA(0.14 mg/kg) was administered in 3 pts(1 as first, 1 as second and 1 as third line therapy); 2 patients underwent HSCT as second and third line respectively. Data about response to treatment are reported in the table. The overall response rate to imatinib was of 30%, registering 1 complete remission(CR) and 4 partial remissions. All but one responsive patients did not present c-kit point mutation. Three pts(10%) died for progression of SM; a fourth patient in CR died for accidental causes. The actuarial Kaplan-Meier curve at 10 years showed an overall-survival of 87%. Conclusions: SM is a rare disease, characterized by severe and life-threatening mediator-related symptoms but with a low mortality rate. D816V c-kit mutation is frequent and associated with resistance against imatinib: only 1 patient showed a CR. Of note 2-CDA has shown interesting clinical response: all 3 treated pts showed a clinical improvement. Because of the rarity of SM, an effective standard of care is lacking. More data are needed to find new and successful therapeutic strategies; it is possible that new tyrosine kinase inhibitors could allow to achieve clinical and molecular remission of disease, crossing resistence to imatinib due to c-kit mutation, in order to improve above all quoad valitudinem prognosis of these pts. Response to treatments. DRUGS CR PR Stable Unrespons. N.E. TOTAL Imatinib 1 4 5 3 4 17 INF-alpha 0 1 1 5 0 7 2-CDA 0 3 0 0 0 3 Conventional CTX 0 1 2 4 1 8 Allo-HSCT 2 0 0 0 0 2 Wait & Watch 0 0 6 2 0 8

Description: Abstract 5032 Introduction. Combining bortezomib with pegylated liposomal doxorubicin for the treatment of Multiple Myeloma (MM) may reciprocally increase their efficacy in vitro and appears to offer higher overall response rates in vivo. With the aim to verify the synergistic interaction towards myeloma cells we planned a prospective study with bortezomib, non-pegylated liposomal doxorubicin and dexamethason in patients with relapsed/refractory multiple myeloma (R/R MM). In this setting of patients, showing a poor outcome because of multi-drug resistance, low-performance status and toxicity to previous chemotherapy, bortezomib, by inhibiting proteasome function, may enhance chemosensitivity to doxorubicin and overcome drug-resistance. Thus, to improve outcome minimizing therapy-related toxicity, bortezomib was added to non-pegylated liposomal doxorubicin and dexamethason (PAD regimen). Patients and Methods. From November 2005 and January 2012, 50 patients with R/R MM (relapsed n= 37 and refractory n= 13) referred to the our Institution received PAD regimen. Male/Female ratio: 27/23; Median age: 61 years (range 34–79); median time from diagnosis: 32 months (range 4–121); median of previous therapy lines: n= 3 (range 1–5); patients previously underwent to autologous and allogeneic hemopoietic stem cell transplantation (auto- and allo-HSCT): 22 and 5, respectively. Planned treatment: bortezomib 1, 3 mg/mq iv days 1, 4, 8, 11; non-pegylated liposomal doxorubicin 30 mg/mq on day 1 and dexamethason 40 mg days 1–4 of a 28-day cycle up to 6 cycles. Results. Forty patients (80%) received the planned treatment schedule whereas 10 patients did not complete it because of toxicity (1 patients) and resistant or progressive disease (9 patients). Median time to best response was 3 months (range 2–6). The overall response rate was 74% with 10 CR (20%), 15 vGPR (30%) and 12 PR (24%). Fifteen of the responder patients underwent HSCT (auto-HSCT: 9; allo-HSCT: 6). The previous use of anthracyclines (35 patients) and bortezomib (3 patients) did not seem influence the response. Median duration of response was 24 months (range 6–57 months). After a median follow-up of 58 months, 14 (28%) patients were alive and, of these, 7 (14%) in Continue CR. The safety profile was manageable: the hematologic grade 3/4 toxicity (neutropenia, thrombocytopenia and anemia) was 28%; non-hematologic grade 3/4 toxicity (sensory or motor neuropathy, infections, fever, fatigue, diarrhea) was 36%. Despite heavy previous treatments, including anthracycline-based, no significant cardiac toxicity was observed. Conclusion. According to our study, the PAD regimen appears feasible and effective in both elderly and heavily pre-treated R/R MM patients. In fact a significant improved clinical outcome in our cohort of patients was observed. Disclosures: No relevant conflicts of interest to declare.