ALBERT

Description: Ca 15-3 is a glycoprotein present in the cells of the mammary carcinoma and in some epithelial cells. Is a marker used for the monitoring of the breast and gastrointestinal carcinoma. The megaloblastic anaemia is an anaemia characterized by deficit of absorption of Vitamin B12 and is associated with gastritis atrophic and the target cell is the parietal gastric cell. In our institution, from June 2003 to December 2004, the level of Ca15-3 and of others tumour markers (CEA; Ca125; Ca19.9; alfa-FETO) they have been tested in the serum of 16 patients (9 male and 7 female with median age of 64,5 and range of 37–80 years) with de novo megaloblastic anaemia, 2 patients were gastrectomized. In all patients has been effected: esophagogastroduodenoscopy and control anti-parietal gastric cells antibody (APCA). Increase level in the serum of CA 15-3 with normal level of other tumour markers have been found in 14/16 patient with median value of 61 U/ml (range 35–100 U/ml) in two patients (gastrectomized) the value of CA 15-3 was normal. Besides in 12/14 patients have shown positivity for the APCA, only in two patients has been diagnosed a gastritis atrophic, in the other patients has been observed a normal gastric mucous. After a median observation of 24 months any patient has developed a mammary or gastro-intestinal carcinoma These results indicate what the increased level of CA 15-3 antigen in patient with megaloblastic anaemia is positively correlated with APCA and with the presence of a normal gastric mucous. These clinical conditions make to suppose the destruction from the APCA of the parietal gastric cells with the liberation of this glycoprotein and this is shown in two patients gastrectomized with presence of APCA and not increased level of the CA 15-3. In conclusion the CA15-3 antigen is probably an specific marker for the diagnosis of megaloblastic anaemia and is probably associated with the destruction of parietal gastric cells.

Description: New drugs and high dose therapy with auto-transplantation (auto-SCT) has improved prognosis of multiple myeloma (MM). New drugs are promising in upfront therapy while the role of maintenance is still debated. Thalidomide (thal) is an active drug in the treatment of myeloma, and is been investigated as first line therapy, the limit of this drug is the toxicity dependent dose and this determines a poor compliance. It could be useful in the control of minimal residual disease. We used low dose of thal as maintenance after autologous transplantation in patient with MM from January 2002 and here we bring our experience after six years of observation. From January 2002 to August 2008 17 patients (8 males and 9 females) with MM have been treated in our institution. Median age was 59,5 years (range 48–72). 10 were IgG, 3 IgA, 3 light chains and 1 plasma-cell leukaemia. Treatment was 4 cycles of VAD regimen followed by auto-SCT. 4/17 performed double auto-SCT. Three months after SCT these patients has begun the maintenance with thal 50 mg/die, to start thal maintenance 9 patients were in CR, 5 in PR and 3 in resistant disease and the median somministration of thal has been of 12 months (range 3–24 months). Median follow up from the beginning of maintenance therapy was 40 months (range 4–76) with 11/17 (64%) patients in CR or stable disease, with progression free survival (PFS) and overall survival (OS) projected at 75 months respectively of 53% and 51% from to start thal. In our experience we have observed a neurological toxicity (grade I–III) in the 65% of the patients but only 4 have had to suspend the treatment; a haematological toxicity of grade I in the 55% of the patients that have not behaved interruption of the treatment and finally in any case we have documented thrombotic episodes. Finally we have compared this group of patients with another group (18 patients) with the same clinical characteristics that we have observed in the same period but that have not effected maintenance with thal. In this last group 13/18 patients (72%) relapsed with median follow-up of 36 months (range 14–75) and median PFS and OS of 16 and 30 months respectively. The difference between the 2 groups is statistically significant for PFS (p: 0.003) and OS (p: 0.04). The median overall survival observed after progression, in the two groups, has been of 13 months in thal group and 17 months in the group of patients that have not effected the maintenance, this difference is not statistically different (p:0.06). In conclusion in 6 years of observation our experience has shown, even if the number of the patients is small, that maintenance with low doses of thal, after auto-transplantation, it not only has a good compliance but it improves the PFS and OS in this cohort and it doesn’t worsen the OS from the relapse.

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: Thalidomide-containing regimens are currently being used as standard initial therapy for both younger and elderly pts with multiple myeloma (MM), but are associated with an increased risk of venous thromboembolism (VTE) which necessitates routine thromboprophylaxis. Controversies exist concerning the best thromboprophylactic regimen to be used in these pts. To address this issue, the Italian Myeloma Network GIMEMA designed a phase III sub-study aimed at prospectively investigating the efficacy and safety of low molecular weight heparin (LMWH) or fixed low-dose warfarin (WAR) or low-dose aspirin (ASA) as prophylaxis against VTE in newly diagnosed MM pts who were randomized to receive primary induction therapy with thalidomide-containing regimens in the context of 2 phase III studies conducted by the same group. In one of these studies, pts with ≤65 years of age were randomly assigned to receive Velcade-Thalidomide-Dexamethasone (VTD) or Thalidomide-Dexamethasone (TD) before autologous transplantation. In the other study, Velcade-Melphalan-Prednisone (VMP) was compared with VMP plus thalidomide (VMPT) for elderly patients aged 〉65 years. The daily dose of Thalidomide was 200 mg in both VTD and TD, and 50 mg in VMPT. Pts randomized to VTD or TD received a total Dexamethasone dose of 320 mg/cycle, while those assigned to VMP or VMPT were given a total Prednisone dose of 240 mg/m2/cycle. By sub-study design, pts treated on VTD or TD or VMPT were randomly assigned to receive thromboprophylaxis with LMWH (Enoxaparin, 40 mg/d) or WAR (1.25 mg/d) or ASA (100 mg/d) for the duration of induction therapy. At the opposite, pts randomized to VMP did not receive any prophylaxis and were used as controls. Sub-study end points included incidence of VTE, acute cardiovascular events, sudden death, bleeding and any other serious adverse events. At the time of the present analysis, 703 pts who received at least 3 cycles of induction therapy were evaluated. Of these pts, 164 treated on VMP were the control group, while the remaining 539 pts (of whom, 209 treated on VTD, 211 on TD and 119 on VMPT) were randomized to receive either LMWH (n=178) or WAR (n=180) or ASA (n=181). Baseline pts characteristics and risk factors for VTE were comparable in all sub-groups. Overall, the risk of VTE was 3.9% with WAR vs 4.5% with LMWH vs 5.5% with ASA (P values not significant for comparisons between different sub-groups), whereas it was 1.8% among the controls. Median times to onset of VTE for pts treated on LMWH or WAR or ASA were 2.66 vs 2.96 vs 2.10 months, respectively. Pts receiving Velcade-containing regimens (VTD or VMPT) had a VTE frequency in the range of approximately 3%, as compared to 5.8% for pts on TD (P value not significant). The rates of cardiovascular events were 0.6% in each of sub-groups including LMWH, WAR and controls, vs 1.1% for pts treated on ASA. No sudden deaths were reported. The incidence of all grades bleeding was 0.6% with LMWH vs 1.1% with WAR vs 3.3% with ASA (P values not significant for comparisons between different sub-groups), while it was 3.7% among the controls. In conclusion, results of the present analysis show that the overall risk of VTE among sub-groups of pts treated with different thalidomide-containing regimens was not superior to that expected during the natural course of MM. No significant relationship was found between the frequency of VTE and thromboprophylactic regimens, induction treatments (e.g. containing or not Velcade) and age of pts (e.g. young vs elderly). In comparison with LMWH and WAR, there was a higher, albeit marginal, risk of VTE and bleeding complications associated with ASA prophylaxis. Finally, a finding not previously well recognized, fixed low-dose WAR was not inferior to LMWH in reducing the risk of VTE among newly diagnosed MM pts receiving thalidomide-containing regimens. For these pts, LMWH, WAR and ASA are likely to be effective thromboprophylactic regimens.

Description: The treatment of acute myeloid leukemia in elderly with age 〉 65 years is still debated. Various reported studies have valued the feasibility of intensive chemotherapy in these setting of patients. The aim of the our study is to value the difference in DFS and OS among 2 groups of elderly patients with AML treated with intensive chemotherapy (IC) or maintenance (M). From June 2001 to May 2005 we have accepted in our Division 45 patients affected by AML aged up to 65 years. 25 were male and 20 were female, with a median age of 75 years (range 67–86 years). 22 patients (12 M and 10 F, median age: 71 years) received intensive chemotherapy (I.C. Flag and MICE) and 23 (13 M and 10 F, median age: 78 years) received or maintenance therapy (low dose cytarabine) or only support. In IC group 11 patients (50%) have obtained to complete remission (CR) with a DSF and OS media of 7,5 and 6,3 months respectively, and a TRM rate of 27%. In the M group the CR has been documented in 6 patients (35%) treated with low dose of cytarabine, with a DFS and OS media of 6,9 and 4,4 months respectively (graph 1–2). This results have shown, as expected, a better CR rate in the IC group, but without any advantage in terms of OS and DFS when compared with the M group. Difference is not statistically significant between the two groups (p: 0.5). Despite a good CR rate, Intensive chemotherapy do not improves survival in elderly patients. This is probably due to the combination of either a high TRM in patients treated with intensive chemotherapy or a high relapse rate. New therapeutics strategies are needed to improve DFS and OS in these patients. Interesting is the use of specific monoclonal antibodies (anti CD33) in this poor risk disease especially in maintenance after a CR obtainable with a low intensive or low dose chemotherapy. Figure Figure

Description: Association between fludarabine (Fluda) and cytosine arabinoside (ARA-C) have shown in a variety of single arm studies an effective antileukemic effect with acceptable toxicity in high risk myelodisplasias and acute myeloid leukemias in elderly patients. In order to increase the synergistic effect of fluda and ARA-C further association (i.e. anthracyclines) or different schedules of administration (i.e. continous infusion) have been performed but not compared. In order to asses if there is an advantage of an association or schedule compared to another we retrospectively analyzed results from two different fludarabine-based regimens administered as front-line therapy in patients with acute myeloid leukemias aged up to 60 years. A total of 42 patients were treated with fluda 25 mg/m2, ARA-C 1 gr/m2 and idarubicin 5 mg/m2 as single day administration for three days (FLAI) or fluda 20 mg/m2 and ARA-C 1,4 mg/m2 as continuous infusion for three days fluda and 4 days ARA-C (c.i.FLA). Total dosage of fluda was 75 mg/m2 in FLAI and 70 mg/m2 in c.i.FLA, while ARA-C total dose was 3 gr/m2 in FLAI and 6,15 gr/m2 in c.i.FLA. Dose administered of idarubicin in FLAI was 15 mg/m2. Patients who obtained complete remission (CR) defined as less of 5% of bone marrow blasts received a second course of the same chemotherapy as consolidation, reduced at 3 days in c.i.FLA. 19 patients were treated with FLAI regimen, 9 males and 10 females, mean age 69,3 years (range 61–75) and 23 received c.i.FLA regimen, 12 male and 11 female, mean age 69,4 years (range 61–84). 4 patients in each group showed unfavourable kariotype. Results were as follows: 8/19 (42%) patients obtained CR after induction with FLAI while 11/23 (48%) were in CR after first course c.i.FLA. Difference is not statistically significative. Median disease free survival (DFS) was 9,53 months for FLAI and 7,67 months for c.i.FLA (p=NS) and median overall survival (OS) in the group in CR was 10.8 in the FLAI group and 10 months in c.i.FLA group (p=NS). Induction deads were 1/19 in FLAI group (5%) and 3/23 in c.i.FLA group (13%). The global median OS, including resistant patients was 6,57 months for FLAI and 6 months for c.i.FLA (p=NS). Two patients in each group underwent autologous bone marrow transplantation in complete remission. Results of the comparison of this two different regimens suggest that there is no substantial difference between single daily administration added of idarubicin and continuous infusion of fluda and ARA-C. Both cycles seem to have the same antileukemic activity with overlapping toxicity. Median time to neutrophil recovery (〉 1000/mmc) was 16 in c.i.FLA and 14,5 in FLAI while platelets recovery (〉 20000/mmc) was 18 in c.i.FLA and 13 in FLAI. Both schedules can be, in our opinion, safely used as front-line therapy in elderly patients affected by acute myeloid leukemias. What is to underline in this setting of patients is the short duration of the CR. Probably some kind of maintenance or association without increasing toxicity is needed, and experience with monoclonal antibodies are an interesting way to follow.

Description: Autologous stem cell transplantation is an efficacy therapy for limphoproliferative disease. However a concern with the procedure is the potential of malignant cells to reinfuse with stem-cell graft. In the past five year, investigators have used rituximab to purge malignant cells in vivo without any manipulation in vitro. From April 2003 to June 2008 we have treated with Autologous stem cell transplantation, purged in vivo with monoclonal antibodies, 24 patients (8 F; 16 M median age: 55 years) with limphoproliferative diseases to poor prognosis (2 Burkitt lymphoma; 3 Burkitt like lymphoma; 4 mantle cells; 3 CLL; 3 NHL-T cells (1 peripheral and 2 lymphoblastic); 2 follicular and 7 large cells) and we have evaluated the results and the feasibility. In all patients, the purged in vivo, has been effected administering a dose of monoclonal antibodies (anti CD20 in B-NHL and anti CD52 in CLL and T-NHL) before the harvest and after the infusion of the stem-cells. To the transplantation 10 patients were in CR (2 Burkitt lymphoma; 3 Burkitt like lymphoma; 2 large cells; 2 NHL-T lymphoblastic and 1 mantle cells) 9 in PR (1 CLL; 3 mantle cells; 2 follicular and 4 large cells lymphoma) and 5 in resistant disease (2 CLL; 2 large cells and 1 NHL peripheral T cells). All patients have harvest (median CD34:4 ×106/Kg) and median minimal residual disease in the harvest has been 〈 to 2%. All the patients have been conditioned with BEAM and the graft are documented in 22/24 patients (2 patients are dead to the day +4 and +10 for gastric haemorrhage and septic shock respectively) with neutrophils〉 1000 in media to day + 11 (range 10–19 days). After transplantation 20/22 patients were in CR, a day +60 the MMR in bone marrow was