ALBERT

Description: We report on a series of 26 patients diagnosed with primary (de novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the clinicobiologic characteristics of the disease together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC, and compared them with 664 multiple myeloma (MM) patients at diagnosis. The median age, sex ratio, and bone lesion extension were similar, but PCL cases displayed a higher prevalence of clinical stage III, extramedullary involvement, and Bence Jones cases, with fewer IgA cases than for MM patients. In addition, according to several prognostic indicators (β2-microglobulin serum level, proportion of S-phase PCs, proteinuria, calcium serum level, lactate dehydrogenase [LDH] and renal function), the incidence of adverse prognostic factors was significantly higher in PCL versus MM. Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20 antigens. Twenty-two PCL cases were diploid and one was hypodiploid, while most MM cases (57%) showed DNA hyperdiploidy. With the fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, −13 (86%), ±1 (57%), +18 (43%), and −X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15. PCL cases had a lower overall response to therapy than MM cases (38% v 63%, P = .01332). Among PCL patients, a trend for a worse response was observed in cases treated with melphalan and prednisone (MP) versus polychemotherapy. Overall survival was significantly worse in PCL versus MM patients (8 v 36 months,P 

Description: In an attempt to reduce toxicity in patients not eligible for standard myeloablative allo-SCT, different RIC regimens aiming to induce an allogeneic graft-vs-tumor (GVT) effect, have been investigated and could result in durable donor cell engraftment. All of these protocols have been shown to be highly immunosuppressive, but because of the variability in degree of myeloablation or inclusion or not of T cell depleting agents such as Campath or ATG, transplant-related events might vary from one protocol to another. We report here a comparison between two prospective RIC strategies for allo-SCT from an HLA-identical sibling in patients with myeloid malignancies (60 AML, 27 MDS and 21 CML). The first RIC regimen (group I, n=56) was based on fludarabine (Flu), busulfan (Bu) and a combined GVHD prophylaxis with CSA and short course methotrexate (MTX; days 1, 3, 6). The second RIC regimen (group II, n=52) included ATG as part of the preparative regimen in addition to Flu and Bu, but used a single GVHD prophylaxis with CSA alone. The kinetic of engraftment was strictly comparable between the two groups: median of 16 days for ANC〉500/μL; 12 (group I) vs. 13 (group II) days for platelet 〉20000/μL. 13 patients (23%) experienced grade 2–4 acute GVHD in group I, as compared to 20 patients (38%) in group II (P=NS). The incidence of extensive chronic GVHD was also comparable between both groups (40% in group I vs. 48% in group II; P=NS). Moreover, 10 patients (18%) in group I died from transplant-related mortality as compared to 11 (21%) in group II (P=NS) with disease progression being the major cause of death in both groups. Both protocols could exert a potent GVT effect, and the incidence of relapse or disease progression was comparable (21%, group I vs. 35% group II; P=NS). In multivariate analysis including protocol type (I vs. II), demographic and disease characteristics and transplant-related events, chronic GVHD was the most powerful protective factor against relapse or disease progression (RR=0.11; P

Description: Recent observations indicate that chromosome aberrations are important prognostic factors in patients with multiple myeloma (MM) treated with high-dose chemotherapy. Nevertheless, the inherent problems of conventional cytogenetics have hampered the systematic evaluation of this parameter in series of patients treated with conventional chemotherapy. Fluorescence in situ hybridization (FISH) analysis is an attractive alternative for evaluation of numerical chromosomal changes. In the present study, we analyze the relationship between aneuploidies of 15 different chromosomes assessed by FISH and prognosis in a series of 63 patients with MM treated with conventional chemotherapy. After a median follow-up of 61 months (range, 6 to 109), 49% of patients are still alive with a median survival of 33 months. The overall incidence of numerical chromosome abnormalities was 70%. This incidence significantly increased when seven or more chromosomes were analyzed (53 patients), reaching 81%. Trisomies of chromosomes 6, 9, and 17 were associated with prolonged survival (P = .033, P = .035, and P = .026, respectively); by contrast, overall survival (OS) was lower in cases with monosomy 13 (as assessed by deletion of Rb gene,P = .0012). From the clinical point of view, loss of Rb gene was associated with a poor performance status; low hemoglobin levels; high creatinine, C-reactive protein, and lactic dehydrogenase serum levels; high percentage of bone marrow plasma cells (BMPC); extensive bone lytic lesions; and advanced clinical stage. Other chromosome abnormalities such as trisomy of chromosome 9 and 17 were associated with good prognostic features including high hemoglobin levels, early clinical stage, β2microglobulin less than 6 μg/mL, and low percentage of BMPC. A multivariate analysis for OS showed that S-phase PC greater than 3% (P = .010) and β2microglobulin serum levels greater than 6 μg/mL (P = .024), together with monosomy of chromosome 13 (P = .031) and nontrisomy of chromosome 6 (P = .048) was the best combination of independent parameters for predicting survival in patients with MM. According to these results, chromosomal analysis is of great use in patients with MM at diagnosis to have a correct prognostic evaluation for clinical decision making.

Description: Although autologous transplant is the election in poor prognosis patients with Non Hodgkin agressive histologies, some patients relapse, for others collection of progenitor cells is not possible and in some categories as Mantle Cell Lymphoma results after autologous transplant are dismal. From 1999, three prospective multicenter trials with non-myeloablative allogeneic transplant in hematological malignancies have been performed in Spain. Up to now, 36 patients have been registered in these trials. From them,28 (58%)had aDBLCL,1 (3%) a transformed MZL,1 (3%) a BL and 14 (37%) a MCL. The conditioning regimen consisted of fludarabine 30 mg /m2 intravenously (IV) on days −8 to −4 followed by melphalan 70–140 mg/m2 IV on days −3 and−2. The last 25 patients enrolled in the latest trial received rituximab 375mg/ m2;on days −8, −1,+8 and +15 as part of conditioning; filgrastim stimulated peripheral blood stem cells were infused on day 0. GVHD prophylaxis consisted of cyclosporine A (CsA) from day −7 plus short-course methotrexate (MTX) (10mg/m2, days +1, +3, +6), followed by folinic acid rescue. Median age was 51 years (range 27–68);at transplant 5 (13%) of the patients were in CR1, 4 (11%) in a later CR and 29 (76%) had active disease 18 (47%) had sensitive disease and 11 (29%) resistant disease. Days to reach more than 500x 109 granulocytes and more than 20000x109 platelets were +14 (range 10–93) and +12(range 8–18). At a median time of 25 days (range 19–97), 19 patients (50%) developed acute GVHD (13 patients (34%) grade II–IV). At a median time of 107 days(80–267), 68% out of 19 patients at risk developed cGVH being extensive in 11 (39%)Disease was evaluated at day +100 and at that moment 23 patients(65%) were in CR (including 4 / 8 patients transplanted on PGR), 4% in PR and 23% have died due to NRM(Non relapse mortality). With a median follow up of 31 months (range: 6–67 months), 19 patients (50%) are alive, 17 disease free and 19(50%) have died, 10(26%) due to NRM and 8 (21%) due to progression with a proyected NRM at 1 year of 22%. OS and EFS at 5 years of of 43 and 36% respectively. None of the variables analysed influenced on NRM. Regarding efficacy of transplant in different histologies, OS and DFS for MCL were 71% and for BDLCL, 31% and 20% respectively. In this preliminary analysis results in MCL are quite good however for patients with DLBCL should be improved. severe toxicity is still present and to date it should be performed only in the setting of well designed clinical trials.

Description: Some studies have suggested that mycophenolate mofetil (MMF) offers a similar efficacy in terms of GVHD prophylaxis as compared to methotrexate (MTX) but a faster engraftment and a lower incidence of mucositis. We have analyzed the results of fludarabine (150 mg/m2) and melphalan (140 mg/m2) or busulphan (10 mg/m2) plus Cyclosporine (CsA) and MMF instead of MTX as GVHD prophylaxis in a series of 30 patients undergoing unrelated allogeneic transplantation. Median age was 44 years (18–60). Patients younger than 40 were required to have a previous comorbid condition (8 had a previous autologous transplant; 2 had proven fungal infection; 1 had severe altered lung capacity). Twelve patients were diagnosed with AML, 4 had ALL, 4 MDS, 2 CML, 3 CLL, 3 NHL, 2 MM/WM. Disease status at transplant was 1st or 2nd CR in 12 patients, 〉2nd CR or PR in 11 patients while the remaining patients had active disease at the time of transplant (relapse, refractory, untreated diasease). Median day to reach 〉 0,5 x 109 granulocytes / L was +17 and to reach 〉 20 x 109 platelets / L was +13. At a median follow up of 445 days among patients alive, projected overall survival (OS) and event free survival at 3 years are 47% and 30%, respectively. Overall TRM was 32%. Cumulative incidence of grades 2–4 and 3–4 aGVHD was 67% and 33%, respectively while cumulative incidence of extensive cGVHD was 70%. Gut was the organ most severely involved in aGVHD in 10 out of 16 patients while liver was involved in only 3 cases. Interestingly, among patients who developed aGVHD, incidence of skin (80%) and liver (22%) involvement were similar to that observed in a similar series of patients receiving related donor transplant using the same RIC plus CsA and MTX instead of MMF while the incidence of gut involvement was significantly higher (64% vs 42%). In conclusion, the RIC used in the current study plus CsA and MMF offers promising results in high risk patients. In terms of GVHD prophylaxis, MMF shows a good efficacy at skin and liver but poor at the gastrointestinal tract.

Description: Recent observations indicate that chromosome aberrations are important prognostic factors in patients with multiple myeloma (MM) treated with high-dose chemotherapy. Nevertheless, the inherent problems of conventional cytogenetics have hampered the systematic evaluation of this parameter in series of patients treated with conventional chemotherapy. Fluorescence in situ hybridization (FISH) analysis is an attractive alternative for evaluation of numerical chromosomal changes. In the present study, we analyze the relationship between aneuploidies of 15 different chromosomes assessed by FISH and prognosis in a series of 63 patients with MM treated with conventional chemotherapy. After a median follow-up of 61 months (range, 6 to 109), 49% of patients are still alive with a median survival of 33 months. The overall incidence of numerical chromosome abnormalities was 70%. This incidence significantly increased when seven or more chromosomes were analyzed (53 patients), reaching 81%. Trisomies of chromosomes 6, 9, and 17 were associated with prolonged survival (P = .033, P = .035, and P = .026, respectively); by contrast, overall survival (OS) was lower in cases with monosomy 13 (as assessed by deletion of Rb gene,P = .0012). From the clinical point of view, loss of Rb gene was associated with a poor performance status; low hemoglobin levels; high creatinine, C-reactive protein, and lactic dehydrogenase serum levels; high percentage of bone marrow plasma cells (BMPC); extensive bone lytic lesions; and advanced clinical stage. Other chromosome abnormalities such as trisomy of chromosome 9 and 17 were associated with good prognostic features including high hemoglobin levels, early clinical stage, β2microglobulin less than 6 μg/mL, and low percentage of BMPC. A multivariate analysis for OS showed that S-phase PC greater than 3% (P = .010) and β2microglobulin serum levels greater than 6 μg/mL (P = .024), together with monosomy of chromosome 13 (P = .031) and nontrisomy of chromosome 6 (P = .048) was the best combination of independent parameters for predicting survival in patients with MM. According to these results, chromosomal analysis is of great use in patients with MM at diagnosis to have a correct prognostic evaluation for clinical decision making.

Description: We report on a series of 26 patients diagnosed with primary (de novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the clinicobiologic characteristics of the disease together with the immunophenotype, DNA cell content, proliferative index, and numeric chromosomal aberrations of the neoplastic PC, and compared them with 664 multiple myeloma (MM) patients at diagnosis. The median age, sex ratio, and bone lesion extension were similar, but PCL cases displayed a higher prevalence of clinical stage III, extramedullary involvement, and Bence Jones cases, with fewer IgA cases than for MM patients. In addition, according to several prognostic indicators (β2-microglobulin serum level, proportion of S-phase PCs, proteinuria, calcium serum level, lactate dehydrogenase [LDH] and renal function), the incidence of adverse prognostic factors was significantly higher in PCL versus MM. Immunophenotypic expression was similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20 antigens. Twenty-two PCL cases were diploid and one was hypodiploid, while most MM cases (57%) showed DNA hyperdiploidy. With the fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases displayed the numeric aberrations, −13 (86%), ±1 (57%), +18 (43%), and −X in women (25%), but they lacked several numeric aberrations usually found in MM such as +3, +6, +9, +11, and +15. PCL cases had a lower overall response to therapy than MM cases (38% v 63%, P = .01332). Among PCL patients, a trend for a worse response was observed in cases treated with melphalan and prednisone (MP) versus polychemotherapy. Overall survival was significantly worse in PCL versus MM patients (8 v 36 months,P