ALBERT

Description: Abstract 3419 Poster Board III-307 Background Bortezomib induction before autologous stem cell transplantation (ASCT) has shown its efficacy in newly diagnosed multiple myeloma (MM) patients, both in association with dexamethasone alone (Harousseau JL, et al. Blood 110, 2007, abstr 450) and in combination with doxorubicin and dexamethasone (Popat R, et al. Br J Haematol 141:512-516, 2008). Lenalidomide, a less toxic and more potent thalidomide-derivative, lacks the neurotoxic effects of the parent drug and represents an optimal agent to include in maintenance regimens. Aims These observations provided the rationale for investigating a sequential approach including bortezomib as induction and lenalidomide as consolidation-maintenance in MM patients undergoing ASCT. Methods A hundred and two newly diagnosed patients aged 65–75 years were enrolled in 17 Italian centers. Induction (PAD) included four 21-day cycles of bortezomib (1.3 mg/m2 days 1,4,8,11), pegylated-liposomal-doxorubicin (30 mg/m2 day 4), and dexamethasone (40 mg/day: cycle 1, days 1–4, 8–11, 15–18; cycles 2–4, days 1–4). Autologous transplantation was tandem melphalan 100 mg/m2 (MEL100) followed by stem-cell support. After ASCT, patients received consolidation with four 28-day cycles of lenalidomide (25 mg/day days 1–21 every 28 days) plus prednisone (50 mg every other day) (LP), followed by maintenance (L) with lenalidomide alone (10 mg/day days 1–21 every 28 days) until relapse. Primary endpoints were safety (incidence of grade 3–4 adverse events [AEs]) and efficacy (response rate). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Time-to-event estimates analysis was performed using the Kaplan-Meier method. Results Very good partial response (VGPR) or better was 58% after PAD induction and increased to 82% after MEL100 and to 86% during LP-L. Complete response (CR) rate was 13% after PAD induction, increased to 38% after MEL100 and to 66% during LP-L. After a median follow-up of 2 years, the 2-year PFS was 69%, the 2-year time-to-progression was 75% and the 2-year OS was 86%. During PAD induction, main grade 3–4 AEs were thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%); treatment-related mortality was 3%. During consolidation-maintenance grade 3–4 AEs included neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). Consolidation-maintenance treatment was well tolerated: only 4% of patients required Granulocyte-colony stimulating factor support and no patient required platelet transfusion; dermatological toxicity was easily manageable with dose-reduction and supportive therapy; no treatment-related deaths were reported. Updated results will be presented at the meeting. Conclusion This is the first phase II study in newly diagnosed MM patients to date, where a sequential approach including bortezomib as induction, and lenalidomide as post ASCT consolidation-maintenance was explored. Treatment was correlated with an increase in response rate and in the depth of response (CR rate) and was generally well tolerated. These data suggest that this is a safe and effective regimen for newly diagnosed MM patients. Randomized trials are needed to confirm these results. Disclosures Patriarca: Celgene: Honoraria; Janssen Cilag: Honoraria. Bringhen:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Janssen Cilag : Consultant, advisory committee, Research Funding; Celgene: Consultant, advisory committee, Research Funding; Pharmion: Consultant, advisory committee, Research Funding. Palumbo:Celgene: Honoraria; Janssen Cilag: Honoraria.

Description: Background: CD is a rare entity characterized by unicentric or multicentric clinical presentation. Three histologic variants (hyline vascular, plasmacell and mixed) have been described. Coexistence of CD and non-Hodgkin (NHL) and Hodgkin’s (HL) lymphomas is well documented in literature; however the last type of association is a rare event. When it occurs, the most frequent association is between interfollicular subtype of HL and plasmacell variant of CD, while there is no agreement regarding a more common combination of HL and either the multicentric or the localized form of CD. Methods and Results: On July 2000, a 33-years-old woman HIV-negative was found to be affected by NS grade I of BNLI cHL diagnosed on a supraclavear nodal biopsy. The final stage was IIIA. After 6 cycles of ABVD and mediastinal radiotherapy, the patient obtained a CR (January 2001). One year later (May 2002) she complained asthenia, but not other clinical signs or symptoms. Laboratory tests revelead increased ERS (49 mm/h) and only mild anemia (11,7 mg/dl). Computerized tomography (CT), ultrasonography (US) and positron emission tomography (PET) showed multiple subdiaphgramatic enlarged lymphnodes in celiac tripod region, haepatoduodenal ligament and interaortocaval zone (2–3 cm of diameter). However, the biopsied nodes obtained by laparoscopy reveled a mixed reactive lymphoadenopathy, but not recurrent HL. During the following 13 months of observation, a further reduction in the hemoglobine value (10.9 mg/dl), increased ERS (87 mm/h) and a very slowly progressive increase in the dimension (4–5 cm diameter) of the abdominal enlarged nodes were documented in the absence of others clinical signs or symptoms. A second nodal biopsy (paracaval lymphnode) was performed in October 2003. Histology showed some lymphoid follicles with small germinal centers(GC), which presented prominent hyalinized vessels and politypical plasmacell component in interfollicular areas indicative of CD (mixed hyaline-vascular and plasmacell subtype). Rare Reed-Stenberg and lacunar cells were found in this background. After the second course of chemoterapy (6 cycles of ABVD) a rapid normalization of ERS and anemia were documented. The CT findings showed a reduction of size and numbers, but no disappereance of abdominal lymph nodes (4 residual nodes of 1–2 cm of diameter). A further nodal biopsy was performed, which confirmed the persistence of HL in the background of CD. Only after RT, the patient obtained a second CR as documented by two subsequent negative CT and PET scans. On July 2005, even if laboratory tests were normal, a single ipogastric superficial lymphadenopathy was detected on phisical examination and confirmed by US: so, a new diagnostic work-up, consisting of PET-SCAN and escixional biopsy is ongoing. Conclusion: After cHL sclero-nodular type, the diagnosis of recurrent HL probably arising on a preexisting multifocal CD, both caracterized by a particularly indolent course, was documented. The two pathogenetic mechanisms hypothized for CD and HL association are: secretion of IL-6 by Hodgkin’s RS cells and/or histiocytes or manifestation of an abnormal immune state associated with Hodgkin’s disease.

Description: Background and aims Present data indicate that FDG-PET has a superior accuracy than gallium scan (Ga-S) in staging and post-therapy restaging of malignant lymphomas. However in Hodgkin’s lymphoma (HL) with a predominant mediastinal involvement and in primary mediastinal lymphoma (ML), this latter, less expensive, nuclear imaging technique might still have a diagnostic value. The aims of this prospective study were to assess: the accuracy of SPET Ga-S in detecting residual tumour in the upper diaphragm nodal regions mainly in the mediastinal site and its predictive value in terms of disease free survival (DFS) and overall survival (OS). Methods Since 1989, 68 patients (pts) with HL (60) or ML (8) were enrolled: 24 male and 44 female. Median age was 28 (range 12-80) years. Ann Arbor stage distribution was: stage IIA in 18 pts, IIB in 23 pts, IIIA in 4 pts, IIIB in 6 pts, IVA in 4 pts and IVB in 13 pts. Histology subgroups included 43 SN, 11 CM, 1 DL, 2 LP, 3 unclassified HL and 8 large B-cell ML. Bulky mediastinal disease was detected in 22 HL and all of ML cases. 44 patients received conventional chemotherapy, 4 non-myeloablative and 20 myeloablative chemotherapy with peripheral blood stem cells support because of unfavourable disease or resistant or relapsing to primary treatment disease. Ga-SPET was performed in all patients 72 hours after the intravenous injection of 370 MBq (8–10 mCi) of 67Ga cirate. SPET data acqusiton included a 360° rotation, with 60 projections at rate of 20 s per projection. The matrix size was 64x64 and a Butterworth filter (0.4–0.6) was used. Results A total of 107 Ga-SPET/TC restaging were obtained after chemotherapy and/or chemo-radiotherapy completion in 64/68 evaluable pts. Despite 84/107 CT evaluations were suggestive of persistent disease in the mediastinal region, 61/107 simultaneous Ga-SPET exams were negative. Instead Ga-SPET indicated the presence of active disease only in 5 cases although the CT was interpreted as negative. Concordant results were documented in the remaining 41 evaluations. The difference in the final post-therapy findings between Ga-SPET and TC were less frequent in upper diaphragm nodal region other than mediastinum, with concordant and discordant results respectively in 51/71 and 20/71 scans. Sensitivity, specificity and accuracy were 89%, 93% and 92% for the Ga-SPET, while they were 100%, 27% and 37% for the CT when the mediastinal area was considered. After a median follow-up of 34 (4–138) months, DFS and OS for patients with a positive Ga-SPET at the end of treatment program were 9 (2–57) and 24,5 (9–67) months, respectively. In contrast, the Corresponding figures have not been reached for patiens with a negative Ga-SPET after a median time of 31,5+ (3–136) months and 49,5+ (4–144) monhs respectively. The median values of DSF and OS of patients with a CT compatible with absent or persistent disease have not been reached at 31+ (3–89) vs 27+ (3–136) months and 46+ (11–108) vs 40+ (4–144) months. Conclusions Thus, Ga-SPET is still a useful, sensitive and not expensive method to determine the presence of eventual active post-therapy disease in the mediastinum.

Description: Fifty-two kariotypic abnormalities additional to Philadelphia chromosome (Ph’) were documented at the time of diagnosis or during the course of the disease in 114 CML patients. Five were evaluated only once at the time of diagnosis, while 109 were repeatedly studied overtime during a median period of 138 (1–275)months. A clonal evolution was already present at diagnosis (early clonal evolution) in 12, while in 23 patients, it was documented in the course of the disease (late clonal evolution). Simultaneous appearence of multiple chromosome abnormalities (4/12 and 4/23) and a tendency to acquire further alterations (5/12 and 2/23, respectively) were associate with both early and late secondary clones. Partial or complete chromosome losses (-1, -6, 6q-, 7p-, 11q-, 12p-, -14, -16, -17,-18, -21) other than -Y (11 events), + 8 (9) and loss of Y chromosome (8) were the most commonly cytogenetic abnormalities, irrespective of the time of their occurrence. Translocations other than Ph’ (5 events), complex Ph’ translocations (5), duplication of Ph’ (5), single iso(Ph’) (4), duplication of iso(Ph’) (1) or iso17q (2) were found with a decreasing frequency. The type of kariotypic alteration varied with the time of onset. In fact, partial or complete chromosome monosomies and duplication of iso(Ph’) never represented early, but only late events. Duplication of Ph’ was a late (4/5) rather than an early event (1/5). Similarly, the presence of the iso(Ph’) was documented either in early or late clonal evolution in 1 and 3 instances respectively. Furthermore, +8 developed several months after diagnosis in all, but 2 cases. Complex Ph’ translocations or loss of Y chromosome do not correlate with any specific phase of the leukemic course. Cytogenetic abnormalities neither correlated with Sokal risk nor with the type of break-points (b3a2,b2a2) documented at diagnosis. However all 3 clones bearing p230 chimeric protein showed early cytogenetic evolution. Secondary clones seem to have different impact on disease history. The occurrence of partial or complete deletions, the iso17q and the late, but not early, loss of Y chromosome were all predictive of a rapid disease progression. Early secondary clones with additional translocations had no effect on the chronic behaviour of the disease, while such clones were associated with a rapid progression (2/3) to blastic phase when they occurred during the course of disease. The presence of +8 as the sole cytogenetic abnormality and complex translocations, irrespective of the time of their onset, did not correlate with leukemia evolution. Finally,simple Ph’ duplication of or single and double iso(Ph’), when not associated with other cytogenetic abnormalities, did not correlate with an aggressive course, even if it can be assumed that these cytogenetic events are responsible for an increased concentration of the p210 oncoprotein. In conclusion, regardless of whether bcr/abl has a direct or an indirect role in promoting genomic instability, in our cohort of CML patients additional non random chromosomal abnormalities frequently characterize both early and late phase of the disease and some of them may represent crucial steps in development and progression of leukemia.