ALBERT

Description: Patients with diffuse large B-cell lymphoma (DLBCL) who develop lymphomatous meningitis (LM) during or after first-line treatment have a poor prognosis, with CNS relapse occurring within 1 year in approximately 80%. Risk factors have been defined and prophylaxis is recommended in patients with high-risk DLBCL. Liposomal cytarabine (DepoCyte®), a sustained-release preparation of cytarabine for intrathecal (IT) injection, has been shown to be well tolerated and effective in the treatment of LM. Its long CSF half-life allows liposomal cytarabine to be given less frequently than conventional therapy, reducing discomfort for patients and the risks associated with repeated lumbar punctures. The potential of liposomal cytarabine to improve the outcome of prophylaxis against LM is being investigated into a multicenter and prospective trial in patients with high-risk DLBCL in Spain. Preliminary safety results are reported in 22 patients (median age 67 years; range 18–79; 14 male) with newly diagnosed DLBCL at high risk of developing LM (defined as the presence of at least one of the following criteria: retroperitoneal mass 〉10 cm, Waldeyer’s ring or paranasal involvement, involvement of 〉30% bone marrow, testicular involvement) who received prophylactic IT liposomal cytarabine during treatment with R-CHOP14 regimen between June 2006 and July 2007 at 10 centers in Spain. Liposomal cytarabine 50 mg was administered during the first day of treatment at first, second and sixth cycles of R-CHOP14 scheme (study days 1, 15 and 71). The median number of doses administered was 3 (range 1–3). Seventeen patients received corticosteroid as prophylaxis for chemical arachnoiditis: 16 dexamethasone (4 mg IT [n = 9] or PO at varying dosages [n = 7]); and 1 patient received IT hydrocortisone (20 mg). The remaining patients did not receive specific corticosteroid prophylaxis for chemical arachnoiditis. Overall, liposomal cytarabine was well tolerated. Six patients experienced minor side effects including headache (Grade 1/2, n = 4; grade 3/4, n = 2) and nausea/vomiting (Grade 3/4, n = 1). No signs of neurological progression or relapsed were observed. These preliminary observations indicate that IT injection of liposomal cytarabine (DepoCyte®) is well tolerated and can be administered safely in combination with dose-dense regimens. Longer-term follow-up will be needed to confirm these encouraging observations.

Description: Genetic abnormalities are one of the most important prognostic factors in CLL. Indeed, p53 deletions/mutations are associated with progressive disease, refractoriness to alkylating or fludarabine (FDR) based regimes and short survival. Similarly, ATM deletion/mutations at chromosome band 11q22.3 are associated with shorter treatment free interval from diagnosis and decreased overall survival. Alemtuzumab (Alem) has shown to be effective in CLL patients (pts) with p53/ATM deletions, when used as a single agent especially in cases with p53 abnormalities. The aim of this study was to evaluate the efficacy of Alem alone or in combination with FDR or MPD in CLL pts with p53/ATM deletions. Materials and Methods: Since Feb/02 to March/07 we have treated 21 pts (15M/6F, median age: 59 yrs, range:48–72) with p53 del (13/21) and ATM del (9/21). Two cases had both types of abnormality. Twenty cases had refractory disease to alkylating or FDR combinations, with a median number of 3 prior regimes. One pts was treated in first line with Alem+MPD. Seven cases had bulky lymphadenopathy (≥7cm). Fifteen pts had Rai stage II, 1 pts stage III and 5 stage IV disease. Eleven pts were treated with Alem 30mg thrice week up to 12 weeks (CAM30), 3 pts with FDR (20mg/m2iv ×3d) + cyclophosphamide (200mg/m2iv ×3d)+ Alem (20mg thrice week iv ×4weeks) every 28d ×2 cycles (FLUCYCAM) and 7 pts with concurrent Alem (30mg thrice week iv ×4weeks) and iv methylprednisolone 1g/m2 days 1–5 every 28d up to 4 cycles (CAMPRED). Hematological responses were evaluated in PB and BM by four color flow cytometry. Genetic abnormalities were screened by G-banding and FISH. P53 mutations were analysed by direct sequencing. Results: Overall, 18(85.7)/21 pts responded to Alem based therapy (6CR, 3nPR, 9PR, 3SD). P53 del was detected at diagnosis in 11/13 cases and ATM del in 6/9 pts. Out of 13 cases with p53del, 5 achieved CR, 1 nPR, 6PR and 1SD. 6 cases also showed associated mutations, but there were no differences in terms of response. Of 9 cases with ATM del, 1 reached CR, 1nPR, 5PR and 2SD. Clinical response according to treatment was as follow: CAM30 (2CR, 1nPR, 7PR, 1SD), FLUCYCAM (1PR, 2SD), CAMPRED (5CR, 3 of them MRD neg, and 2PR). Progression free survival (PFS) was 6 months, 3 months and not reached for CAM30, FLUCYCAM and CAMPRED regimes respectively. Infusional side effects were present in 80% of cases, myelotoxicity was more frequent with FLUCYCAM (100%) than CAM30 (30%) and CAMPRED (25%). Infections were seen in 42% of cases and CMV reactivation in 34%. 2 pts died of gram- sepsis. Richter transformation EBV+ was seen in 6(28%)21 pts and did not correlate with the number of prior treatments or with the type of genetic abnormality. Conclusion: Alemtuzumab in monotherapy demonstrates clinical activity in CLL patients with p53 and ATM deletions, although this response is transient in most cases and less effective in patients with lymphadenopathy. The association with fludarabine shows similar effects but more toxicity. However, the combination with methilprednisolone is more effective in eradicating PB and BM lymphocytes and also on bulky lymphadenopathy in patients with p53 and ATM abnormalities.

Description: Rituximab in combination with CHOP-like chemotherapy has demonstrated to improve the results in young and elderly patients with DLBCL compared to chemotherapy alone. Re-treatment with rituximab is feasible in patients with indolent lymphoma, but there is few data on the effect of rituximab in combination with chemotherapy in the re-treatment of relapsed patients with DLBCL who have respond previously to rituximab + chemotherapy. In order to investigate the effect of rituximab in this setting, we have performed a multicenter retrospective study in 50 patients with DLBCL re-treated with rituximab in combination with chemotherapy. We have included in this study 46 patients (31 males, 15 females), median age 60 (range, 20 to 81 years), who achieved CR with the previous rituximab-containing regimen. At initial diagnosis, 32 patients had Ann-Arbor stage III or IV and 20 patients had IPI 3 or 4. The median interval between courses was 14.7 months. The most frequent regimens administered as up-front therapy in combination with rituximab were CHOP-like regimens (30 patients) and the commonest chemotherapy regimens used as salvage therapy were R-ESHAP (20 patients), R-ICE (7 patients), rituximab in combination with gemcitabine-based regimens (4 patients) and TTR (3 patients). The overall response rate in the assessable population was 81% (46% CR, 35% PR). In 25 assessable patients who have received rituximab in combination with chemotherapy as second-line therapy, the overall response rate was 92% (56% CR, 36% PR). The overall response rate was slightly lower in those patients re-treated with rituximab as third-line therapy (78% with 33% CR and 45% PR). The follow-up is too shorter (median 6 months) to assess the impact of re-treatment on duration of remission. The adverse events were not different to those usually observed with these regimens. In conclusion, the re-treatment with rituximab in relapsed patients with DLBCL who had respond previously to rituximab in combination with chemotherapy seems not to compromise the results in terms of response. Logically, larger prospective studies are necessary to confirm these encouraging results.

Description: Treatment with FCM results in responses rates of 60% in relapsed or refractory CLL patients. Against this background, we started a trial of FCM in untreated patients diagnosed with CLL younger than 65 yrs. FCM consisted of fludarabine 25 mg/m2 i.v. on days 1 to 3, cyclophosphamide 200 mg/m2 on days 1 to 3, and mitoxantrone 6 mg/m2 i.v. on day 1, given at a 4-week intervals up to six courses. Patients received support with G-CSF and prophylaxis with cotrimoxazole. Response was assessed two months after treatment and included bone marrow and minimal residual disease (MRD) analysis by four-color flow cytometry and PCR. Out the 64 evaluable patients (74% male, median age 58 years), 83% were in advanced (B and C) Binet’s clinical stage and 62% had increased (〉20%) ZAP-70 expression. FISH analysis disclosed del(13q) in 25%, +12 in 22%, del(17p) in 10% of cases and del(11q) in 23%. Eighty-three per cent of the patients received the entire planed treatment. Overall response rate was of 88%. MRD-negative CR was obtained in 24%, MRD-positive CR in 23%, nPR 22% and PR 11%. Two out of 14 nPR cases were MRD-negative. Duration of response was 55% at 36 months. Initial parameters associated with CR achievement were the presence of del(17p) (p=0.003), increased serum LDH (P=0.014), and splenomegaly (p=0.04). Hematological toxicity was mild, with grade III-IV neutropenia in 8% of the cases, and moderate infections in 12%. Two patients developed fulminant B hepatitis, one of them dying as a direct consequence of it. In conclusion, in untreated CLL patients, FCM induces a high CR rate, including an important number of MRD negative CR. This places FCM among the most effective regimens for CLL and serves to build up a new immunochemotherapy regimen for CLL (R-FCM) currently under investigation.