ALBERT

Description: Abstract 2887 Poster Board II-863 Between November 2002 and April 2006, 72 patients with Waldenstrom's Macroglobulinemia (WM) were enrolled into this multicenter trial of primary treatment with DRC which consisted of dexamethasone 20 mg IV followed by rituximab 375mg/m2 IV on day 1 and oral cyclophosphamide 100 mg/m2 bid on days 1 to 5 (total dose 1000 mg/m2). DRC courses were repeated every 21 days for six courses and then patients without progressive disease were observed without treatment. Patient characteristics, toxicity and response data have been reported previously (Dimopoulos et al, J Clin Oncol 2007; 25:3344): 83% of patients achieved a response including 7% complete, 67% partial and 9% minor responses. In June 2009 we updated this study (minimum follow-up 〉3 years) in order to assess time to progression, time to next treatment, type of second-line treatment and response to this, overall survival (OS) and cause-specific survival (CSS) in which deaths unrelated to WM or complications of treatment were censored. Second line treatment was administered to patients who experienced progressive disease and also met criteria for treatment requirement based on consensus recommendations (Kyle et al, Sem Oncol 2003; 30:116). As of June 2009, 42 patients fulfilled the criteria for progressive disease (Kimby et al, Clin Lymphoma Myeloma 2006; 6:380) but 14 patients have not yet required second line treatment. The median time to progression was 35 months (95% Confidence Interval: 22-48 months) and the median time to next treatment requirement was 51 months. Among several factors who were analyzed for their possible correlation with shorter time to progression, only lymphadenopathy was significant (p

Description: Rituximab is a chimeric anti-CD20 monoclonal antibody, which targets both, autoreactive and neoplastic B-lymphocytes, thus representing a rational therapeutic approach for patients with various autoimmune disorders. However, although rituximab has been used asa treatment option for patients with autoimmune blood cytopenias, its optimal use has not yet been established. In an effort to analyze the effectiveness and safety of rituximab treatment in this patient population, we have retrospectively analyzed treatment outcome of 147 patients with various autoimmune blood cytopenias or related disorders (AutoImmuneHemolytic Anemia-AIHA N=31, Immune Thrombocytopenic Purpura-ITP N=67, Thrombotic Thrombocytopenic Purpura-TTP N=32, Evans’ Syndrome-ES N=10, Acquired Hemophilia-AH N=4, Anti-Phospholipid Syndrome-APS N=2 and Immune Neutropenia-IN N=1). Eligible patients should have received at least 3 courses of rituximab treatment, unless would have been died earlier due to treatment-related causes. Patients were 68 male and 79 female, with a median age of 52 years (range 15-87 years) and were treated following 1-7 (median 2) lines of previous treatment, for an early (12 months, N=39) or for refractory disease (N=48), at a median of 3.4 months following initial diagnosis (range 0.1-430 months). Eighteen patients received rituximab as first-line treatment due to contra-indication (N=10) or intolerance (N=8) of corticosteroids. Rituximab was administered at the classical dose of 375 mg/m2 (N=113) or at a reduced dose of 200 mg/m2 (N=26), whereas 8 patients initially received 375 mg/m2 for 1-6 cycles and continued with the reduced dose. Each patient received a median of 6 courses of rituximab (range 1-60 courses). Four out of 143 patients were HBsAg positive, and 62/133 were anti-HBc positive. These patients received lamivudineprophylaxis,throughout rituximab treatment and up to 6 months following rituximab withdrawal. Seven patients (4.8%) received

Description: The FCR combination in a phase III study (Blood 102, abstract #373, p110a,2003) has shown promising results in the treatment of chronic lymphocytic leukemia (CLL) patients leading in increase of proportion of complete remissions and improved survival. Based on these encouraging results we tried to study the efficacy and safety of the FCR combination in patients of our Haematologic Unit. Seventeen patients, 8 males and 9 females with a median age of 69,5 years old, with relapsed/refractory or de novo CLPD ( 9 CLL and 8 NHL patients) were enrolled in this study between February 2002 and August 2004. Fifty percent of CLL patients had Rai stage I/II and the rest 50% had Rai stage III/IV disease. Four NHL patients had also Ann Arbor stage I/II and the rest four Ann Arbor stage III/IV disease. They were treated with Rituximab 375 mg/m2 on day1 in combination with Fludarabine and Cyclophosphamide ( 25 mg/m2 and 250 mg/m2 respectively) for days 2 to 4, every 4 weeks, for 6 consecutive cycles. Nine patients had a history of a prior unsuccessful treatment. Overall, 14 out of 17 evaluable patients were responsive to the treatment [12 patients complete response (CR) and 2 patients partial response (PR), overall response rate (ORR) 82%]. The remaining 3 patients did not show any response (NR), 2 progressive and 1 stable disease. Hematological toxicity was acceptable ( grade 2–3 neutropenia in 6/17 patients, grade 2–3 anemia and thrombocytopenia in 2/17 patients). There were no septic episodes except one case with neutropenic fever. There were no adverse events like nausea or vomiting except one patient with a serious anaphylactic reaction due to Rituximab administration. Three CLL patients died because of stable or progressive disease. In conclusion, this preliminary report suggests that the FCR regimen is an effective and safe treatment for CLPD patients, achieving higher CR rates than previous treatments. A longer follow up of a larger number of patients is required to confirm an improved survival in these patients.

Description: Abstract 3032 The treatment of Waldenström's Macroglobulinemia (WM) has changed over the last decades, mainly since the introduction of nucleoside analogues and of rituximab in the management of this disease. Furthermore, novel agents such as bortezomib have been recently introduced. Several analyses in multiple myeloma indicated that the outcome of these patients has significantly improved over the last decade as a result of the introduction of novel agents. However, such data are not available for patients with WM. Thus, we performed an analysis in order to investigate whether the outcome of patients with WM has improved over the last years, compared to that of patients who started treatment before new drugs, such as rituximab became widely available, especially as part of the frontline treatment. We analyzed the database of the Greek Myeloma Study Group which includes 345 patients, who started treatment after January 1985: 130 patients initiated treatment before 1/1/2000 (Group A) and 215 patients started treatment after 1/1/2000 (Group B). More patients were males in both groups (54% in group A vs. 63% in group B, p=0.084), but patients in group B were older (median age 70 years vs. 65 years in group A, p=0.001). Patients in both groups started treatment mainly due to anemia (40% and 43% in groups A and B, respectively). Similar percentages of patients in groups A and B had hemoglobin ≤11.5 g/dl (74% vs. 77%, p=0.57), platelets ≤100,000/ml (12% vs. 14%, p=0.643), albumin ≤3.5 g/dl (44% vs. 50%, p=0.306) and elevated LDH (≥250 IU/L) (21% vs. 17%, p=0.422). The median serum M-peak levels were also similar (3.95 g/dl vs. 3.75 g/dl, p=0.485) while 5% and 7% of patients in groups A and B had a serum M-peak 〉7 g/dl (p=0.491). However, more patients in group B had serum beta2-microglobulin above 3 mg/dl (62% vs. 42%, p=0.004). Thus, according to the International Prognostic Scoring System (IPSS) for WM, 30%, 48%, and 22% had low, intermediate and high risk disease in group A and 15%, 42% and 43% in group B, respectively (p

Description: Abstract 3036 The ISS introduced by Greipp et al (J Clin Oncol 2005) represents today the most widely used staging system for patients with multiple myeloma (MM) because it is based on two readily available variables: serum albumin and beta2-microglobulin. Serum beta2-microglobulin not only reflects myeloma tumor load but it is also increased in patients with renal dysfunction. Thus, there have been concerns that ISS-3 stage may include MM patients with renal impairment in whom elevated beta2-microglobulin does not reflect tumor burden but rather the degree of renal dysfunction. To address this issue, we assessed the impact of patients' renal function on the prognostic performance of ISS. Our analysis included data from 1516 patients with symptomatic MM that had been entered into the database of the Greek Myeloma Study Group. Renal function was assessed by the estimated GFR (eGFR), which was calculated using the modified MDRD formula (eGFR in mL/min/1.73 m2 = 186 × (Serum Creatinine)−1.154 × (Age)−0.203 × (0.742 if female) × (1.212 if African-American) and the degree of renal dysfunction was staged according to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (KDOQI) classification of chronic kidney disease (CKD) as follows: stage 1 eGFR ≥90 ml/min; stage 2 eGFR of 60–89 ml/min; stage 3 eGFR of 30–59 ml/min; stage 4 eGFR of 15–29 ml/min and stage 5 eGFR

Description: The Greek Registry of Myelofibrosis (MF) is held under the auspices of the Acute Leukemias and Myeloproliferative Neoplasms Study Group of the Hellenic Society of Hematology. The preliminary results after two years of retrospective data collection are presented. The total number of patients included is 226, from 10 Greek sites; the initial diagnosis was made between 1975 and 2013. The male to female ratio was 1.66. Median age at diagnosis was 69 years (range 25-88). In 26% of patients myelofibrosis was secondary to pre-existing hematological malignancy (essential thrombocythemia in 60%, polycythemia vera in 31%). The most prevalent presenting symptoms as reported by the treating hematologist were related to anemia (48%), enlarged spleen (33%), leukocytosis (18%) or thrombocytosis (16%) in routine blood counts examination and beta-symptoms (14%), followed by thrombocytopenia (7.3%), leukopenia (5.3%), thrombosis (3.4%), hemorrhage (2.4%), erythremia (1.5%). As documented in patient records at diagnosis, median platelet counts (PLT) were 283x109/L, hemoglobin (Hb) 10.3 g/dL, white blood cell counts (WBC) 10.5 x109/L and the spleen was palpable in 86% of patients. According to the International Prognostic Score System (IPSS), patients were categorized as low risk (15.8%), intermediate-1 (32.3%), intermediate-2 (32.3%) and high risk (19.6%). Molecular studies were performed in 77 patients (34% of total) and 69% of them were positive for the JAK2-V617F mutation. The therapeutic strategy in myelofibrosis is dictated by the symptoms present and can be a combination of agents. In the Greek Registry, all but 7% of patients have required treatment. First-line therapy was a single agent in 68% (hydroxyurea 34%, erythropoetin 19%, androgen 11%, interferon 4%, corticosteroids 3%, ruxolitinib 2%) and a drug combination in the remaining 32%. Taking combinations into account, hydroxyurea was given to 41%, erythropoetin to 31%, androgens to 16%, corticosteroids to 8% and anagrelide to 2% of patients. In second-line therapy, combinations were administered to 50% of patients and they included erythropoetin (27%), androgens (22%), hydroxyurea (15%) or corticosteroids (15%); monotherapy with interferon was given to 6% and ruxolitinib to 4% of patients. At any time during the disease course, splenectomy was performed in 5% and spleen irradiation in 12% of patients for symptom relief. Data for secondary malignancies were available in 170 patients. Acute leukemia occurred in 8% and solid tumor in 5% of patients. Survival information is available for 147 patients. Median overall survival was 4.46 years, whereas 5- and 10-year survival rates were 45.3% and 11.5% respectively. The aim of the registry and the subsequent data analysis is to convey the practice of managing the disease. Moreover, useful conclusions can be reached regarding to the patients’ responsiveness to therapy and the parameters that correlate with overall survival and disease progression. Disclosures No relevant conflicts of interest to declare.

Description: Purpose: We have previously reported that diffuse pattern of bone marrow involvement as determined by MRI imaging of the spine, in newly diagnosed patients with MM is associated with features of advanced disease and with shorter survival compared to patients with normal, focal or variegated pattern of BM involvment. Purpose of the study was to determine the prognostic value of spinal bone MRI in the outcome of MM patients undergoing treatment with HDM and ASCT. Materials and methods: Between October 1995 and June 2006, 63 MM patients for whom a MRI of the spine before first line therapy was available, received treatment with HDM (200mg/m2 iv) and ASCT, in our Department. Four patterns of BM involvement in MRI were identified: normal pattern which required no evidence of abnormal signal, focal pattern, which consists of localized areas of abnormal marrow (on T1-weighted images, focal lesions are darker than yellow marrow and slightly darker or isointense to red marrow; on T2-weighted images they are brighter than both red and yellow marrow), diffuse pattern of abnormal marrow, where the normal bone marrow is completely replaced by the abnormal process and the intervertebral discs appear brighter or are isointense to the diseased marrow, and variegated pattern, which consists of innumerable small foci of disease on a background of intact marrow. MRI pattern of BM involvement and multiple clinical and laboratory parameters were evaluated for their possible correlation with progression free survival (PFS) after HDM. Results: Patients’ median age was 55years (range: 23 to 74 years), 60% of patients had ISS 2 or 3 before initial treatment, 54% of patients were transplanted during remission and 46% of patients had active myeloma at the time of HDM (primary refractory: 34%, resistant relapse: 12%). Nine patients (14%) had a normal MRI pattern, 33 (53%) had focal, 4 (6%) variegated and 17 (27%) diffuse MRI pattern of BM involvement. The median PFS for all patients was 20 months. Significant adverse prognostic factors for PFS included elevated creatinine and LDH serum levels, and ISS stage 3 at diagnosis. Furthermore the pattern of BM involvement by MRI correlated strongly with PFS: median PFS of 72 months for normal pattern, 20 months for focal pattern, 16 months for variegated and 9 months for diffuse pattern (p=0.016). Patients with both ISS stage 3 and diffuse MRI pattern had a median PFS of only 6 months. Conclusion: MRI of the spine before treatment provides prognostic information for the outcome of MM patients with myeloma after HDM and ASCT. Diffuse marrow replacement on MRI of the spine identifies patients with advanced MM who have a poor prognosis even after intensive therapy. Such patients are candidates for innovative treatments.

Description: Bortezomib (V) and thalidomide (T) exert their anti-myeloma (MM) action partly through perturbation of the MM microenvironment. The aim of this phase II study was to determine the efficacy and safety of the combination of VT with melphalan (M) and dexamethasone (D) and its effect on angiogenesis and bone remodeling in relapsed/refractory MM. Bortezomib (1.0 mg/m2) was given iv, on days 1, 4, 8, and 11; oral melphalan (0.15 mg/kg) was administered on days 14, while thalidomide (100 mg/day) and dexamethasone (12 mg/m2) were given on days 1–4 and 17–20 of a 28-day cycle, for 4 cycles. Patients without progression continued for up to 8 cycles. Effect of VMDT on angiogenesis was evaluated by measuring serum levels of VEGF, angiogenin (ANG), angiopoietin-2 (ANGP-2), and basic fibroblast growth factor (bFGF) at baseline and after 4th and 8th cycle. Bone remodeling was studied by the measurement of serum indices:osteoclast stimulators [sRANKL, osteoprotegerin (OPG), osteopontin, MIP-1α],osteoblast inhibitor, dickkopf-1 (DKK-1),bone resorption markers [C-telopeptide of collagen type-I (CTX), tartrate resistant acid phosphatase-5b (TRACP-5b)], andbone formation markers [bone alkaline phosphatase (bALP), osteocalcin (OC), and CICP].Among 60 pts registered in this study, 53 have completed 4 courses of therapy as of June 2006 and form the basis for the current analysis. Median time from 1st treatment to VMDT was 36 months. The median number of previous treatments was 2 (range: 1–7). Prior agents included V (11%), M (43%), D (100%), T (56%), and ASCT (30%). The objective response rate was 60%(32/53 pts): CR 11%, vgPR 26% and PR 22%. Furthermore, 6 pts (11%) achieved a MR and 8 SD. Median time to response was 35 days. Median PFS was 9.5 months with a median follow-up period of 12 months. Adverse events included fatigue (58%), thrombocytopenia (20% grade 3/4), neutropenia (8% grade 3/4), anemia (5% grade 3), neuropathy (50% grade 1/2, and 7% grade 3), infections (45%, including 5 HZV cases), and hyponatremia (15%). No patient experienced DVT, while 2 pts died due to sepsis and one due to necrotizing fasciitis. At baseline, MM patients had increased serum levels of DKK-1, sRANKL, sRANKL/OPG ratio, MIP-1α, CTX, VEGF, ANG, ANGP-2, and bFGF (p

Description: Introduction: Thalidomide is usually administered orally continuously once daily and has shown remarkable activity in about 30% of patients with heavily pretreated multiple myeloma (MM). Moreover, there is considerable interest in the administration of thalidomide-containing combinations as primary treatment of MM. With such regimens at least 60% of patient achieve an objective response. Thalidomide can cause a variety of side effects whose incidence and severity may be related to the maximum dose and duration of thalidomide treatment. Furthermore, this drug may be poorly tolerated by older patients. We designed a phase II study for the primary treatment of elderly patients (≥ 75 years of age) with MM which was based on intermittent oral administration of melphalan, thalidomide and dexamethasone. Patients and Methods: This ongoing multicenter study was initiated in February 2003 and includes patients with symptomatic myeloma ≥75 years of age regardless of performance status, renal function, and comorbidities. Treatment consists of melphalan (M) 8mg/m2 days 1–4, dexamethasone (D) 12mg/m2 p.o. after breakfast on days 1–4 and 14–18 and thalidomide (T) 300 mg p.o. at bedtime on days 1–4 and 14–18. This regimen is repeated every 5 weeks for 3 courses. Patients without evidence of progressive disease are scheduled to receive 9 additional courses of MDT (but without DT on days 14–18) every 5 weeks. Results: As of July 2004, 43 patients have been enrolled. Their median age is 78 years (range: 75 to 85 years). Features of advanced myeloma are frequent and include International Staging System (ISS) 3 in 58%, hemoglobin 11.5 in 15%, creatinine 〉 2 mg/dl in 28% and elevated serum LDH in 11%. On an intent-to-treat basis, 72% of patients achieved at least a partial response (EBMT criteria) including 10% of patients who achieved a complete response with negative immunofixation. Median time to 50% reduction of monoclonal protein was 2 months (range 0.5 to 5.5). Grade 3 or 4 granylocytopenia and thrombocytopenia occurred in 15% and 10% of patients respectively. Twelve episodes of infections were noted one of which was fatal. Several patients developed thalidomide-related side effects, usually of mild or moderate degree, such as constipation (30%), somnolence (35%), tremor (25%), xerostomia (15%), headache (10%). Deep venous thromosis (DVT) and peripheral neuropathy occurred in 10% of patients each. With a mean follow-up of 15 months, 88% of patients remain alive. Conclusions: This is one of few prospective studies designed for myeloma patients with advanced age (≥75 years) ie patients who are frequently excluded from trials. The pulsed MDT regimen appears to be a well tolerated and active primary treatment for elderly patients with multiple myeloma. The incidence of DVT and of peripheral neuropathy appears lower than that seen when thalidomide is administered continuously. Patient accrual and follow-up is ongoing in order to assess the impact of this regimen on response duration and survival.

Description: Introduction - Aims: Several prognostic scoring systems have been developed for patients with myelodysplastic syndromes (MDS), including the International Prognostic System (IPSS), the WHO Prognostic Scoring System (WPSS) and the Revised IPSS (IPSS-R). We evaluated the prognostic value of the IPSS-R on an independent group of 2,582 Greek patients with MDS, registered in the Hellenic National MDS Registry. The aim of this multicenter study was to validate the IPSS-R as a predictor for leukemia-free survival (LFS) and overall survival (OS), in newly-diagnosed MDS patients and to compare its prognostic significance with that of IPSS and WPSS. Moreover, to investigate the predictive value of IPSS-R in association with other recognized prognostic variables, such as patient's age, baseline serum lactate dehydrogenase (LDH), and ferritin concentrations, IPSS, WPSS, Eastern Cooperative Oncology Group (ECOG) performance status, transfusion dependency, and response to first-line treatment. Methods: Clinicopathological data from 2,582 MDS patients, diagnosed between 1/2000 - 1/2015 and registered in the Hellenic National MDS Registry were analyzed. Patients with MDS/MPN were excluded. Data included age, gender, date of diagnosis, clinical characteristics, WHO-2008 classification, laboratory parameters, transfusion dependency, bone marrow aspirate and biopsy morphology, cytogenetic findings, and type of treatment. LFS was calculated from the date of initial diagnosis of MDS until bone marrow blast increased to ≥20% [transformation to acute myeloid leukemia (AML), according to the WHO classification], or last contact. OS was defined as the time from MDS diagnosis to death, or last contact. Patients alive and not having developed AML until last follow-up were censored for OS and LFS, respectively. Kaplan-Meier survival analysis and Cox regression analysis were performed with regard to LFS and OS. Differences between Kaplan-Meier curves were evaluated using the Mantel-Cox (log-rank) test. All significant variables identified by univariate Cox regression analysis and clinical factors important for MDS were used to build the multivariate Cox regression models. Multivariate Cox regression analysis included only those patients for whom the status of all variables was known, and comprised age, serum LDH, and ferritin levels, transfusion dependency, response to first-line treatment, IPSS, WPSS, and IPSS-R. Confidence intervals (CI) were estimated at the 95% level; all tests were two-sided, accepting p