ALBERT

Description: Alemtuzumab is the standard therapy for treatment of patients with relapsed/refractory B-CLL. Significant responses have also been documented in the front-line CLL setting, and as well as in first-line therapy of patients with T-PLL, a population with an exceptionally poor prognosis and few available therapeutic options. Limited data available on the therapeutic benefit of alemtuzumab in other aggressive lymphomas such as B-PLL, which is rare, with a heterogeneous clinical course, and often chemoresistant, as well as CLL with Richter’s transformation, which is also characterized by a poor clinical outcome. Here, we present data on safety and efficacy of alemtuzumab in 6 patients with B-PLL, and 2 cases of B-CLL with Richter’s transformation, both of which developed into DLBCL; one B-CLL case was atypical due to negative CD5 expression (CD19+, CD5−, CD23−). Median age for all 8 patients was 62 years (range, 58–72 years), 5 were male, and all had received a median of 3.5 prior therapies (range, 0–11). Two patients were Rai stage II and III, respectively, and 4 had Rai stage IV disease. At baseline, 3 of the 6 patients with B-PLL had poor performance status, as evidenced by exceptionally high leukocyte counts with clinical signs of hyperleukocytosis and fever of unclear origin. IV alemtuzumab 30 mg was administered according to guidelines (3 times a week, 12 weeks scheduled), but in the majority of cases, dosing was individualized. The median duration of therapy was 4.5 weeks (range, 1–12 weeks), and the median dose was 348 mg (range, 3–793 mg). Therapeutic response was determined according to NCI-WG criteria. In the 2 of 3 patients with poor PS at initiation of therapy an objective response could not be determined due to an early death (septicemia with staphylococcus); 1 patient died prior to achieving a full response due to a suspected apoplectic insult, and another patient died due to progressive disease, shortly after starting alemtuzumab. However, 2 (33%) patients with B-PLL achieved stable disease, lasting 7 months in both cases. Both patients gained a clear clinical benefit from treatment with alemtuzumab as evidenced by CR and PR in peripheral blood, individually, and transfusion independence in both patients. These 2 patients appeared to have favourable disease characteristics, as has been described by other investigators (Leukemia & Lymphoma1999; 33:169), and were diagnosed 9 and 11 years before alemtuzumab, respectively. In the 6 B-PLL patients, overall survival (OS) after start of alemtuzumab therapy was very heterogeneous (0.1; 0.2; 0.3; 1; 27+; 28 months), with a longer OS in the 2 patients with SD. In the 2 patients with B-CLL/Richters’s syndrome (as multifocal DLBCL), PD was observed in one after 2 months on alemtuzumab (survival 15 months). The patient with atypical features was receiving alemtuzumab as an 8th line of therapy and achieved a PR lasting for 13 months (OS 31+ months). In summary, we are adding evidence of therapeutic efficacy of alemtuzumab in a subset of patients with rare, chemotherapy refractory B-lymphoproliferative diseases.

Description: Abstract 2871 Poster Board II-847 Introduction: AL amyloidosis is characterized by misfolding of structurally unstable light chains that form deposits in various organs thereby causing impaired organ function. Treatment of AL amyloidosis remains challenging and is primarily directed towards the underlying abnormal plasma cell clone. Novel agents with proven efficacy in multiple myeloma like the proteasome inhibitor bortezomib have also shown initial promising results in patients with AL amyloidosis, but its value needs to be further established. In this retrospective analysis, we have collected data regarding efficacy and tolerability of treatment with bortezomib plus dexamethasone in patients with AL amyloidosis. Patients and Methods: 25 patients with histologically proven systemic AL amyloidosis were included in this analysis. All patients received bortezomib at a standard dose of 1.3mg/m2 (days 1, 4, 8, 11 of a 3-week cycle) in combination with dexamethasone (8mg to 20mg administered on the day of bortezomib and the day after). Routine clinical and laboratory parameters including evaluation were obtained on a monthly basis. Results: Patients (male n=13, female n=12) were at a median age of 57 years (range 42-83), and 17 patients (68%) received bortezomib/dexamethasone as their first line treatment. The majority of patients had an ECOG performance status of 〈 2. Twelve patients (48%) had only one organ involved, whereas 〉 2 organs were involved in 6 patients (24%). Organs most frequently involved were kidneys (100%), heart (28%), liver (12%) and the gastrointestinal tract (12%). At the time of analysis, a median of 3 cycles of bortezomib/dexamethasone (range, 1 to 8) have been administered. A hematologic response was observed in 14 patients (56%) including 5 patients (20%) qualifying for a complete response (CR). All CR patients received bortezomib/dexamethasone as their first line treatment, and parameters of organ function also improved in these patients. Median overall survival has not yet been reached after a median follow-up of 12 months. Grade 3 and 4 toxicities were rare and consisted predominantly of transient thrombocytopenia. Grade 2 neurotoxicity was observed in 24% of patients. Other grade 1/2 toxicities observed at higher frequencies included hypotension (16%), edema (16%), and fatigue (12%). Conclusion: Our results confirm the activity of bortezomib/dexamethasone in patients with AL amyloidosis (hematologic response rate 56% including a 20% CR rate). Disclosures: Ludwig: Celgene: Honoraria; Mundipharma: Honoraria; AMGEN: Honoraria; Ortho-Biotech : Honoraria; Janssen-Cilag: Research Funding; Roche: Honoraria.

Description: Thalidomide-Dexamethasone (TD) is an active regimen in patients with relapsing/refractory multiple myeloma (MM). Recent phase II and III studies revealed an even higher response rate in previously untreated patients. In the present trial we compare TD with standard Melphalan-Prednisone (MP) in previously untreated elderly patients with multiple myeloma. The trial is designed to include 350 pts with MM, 190 patients have been enrolled so far (median age: 72 years, stage I: 9 (5%), stage II: 61 (32%), stage III: 120 (63%). Patients are randomized to Thalidomide 200mg/day and Dexamethasone 40mg, days 1–4 and 15–18 (on odd cycles) and days 1–4 (on even cycles) or Melphalan 2.5mg/kg day 1–4 and Prednisone 2mg/kg days 1–4, q 4–6 weeks. Thalidomide should be dosed up to 400mg/day, if feasible. Patients achieving response or stabilization are randomized to maintenance treatment either with Thalidomide (maximal dose 200mg/day)-Interferon alpha-2b (3Mega U, TIW) or Interferon alpha-2b (3Mega U/TIW). All patients are scheduled for monthly Zometa (4mg) during the entire period. Response is defined according Blade’s criteria, statistical results are given by intend to treat analysis. 125 patients are evaluable for response as yet. Best response to TD was: CR 6 (10%), NCR 7 (12%), and VGPR 9 (15%) PR 9 (15%), MR 10 (16%) yielding an ORR of 67%. Four pts had SD (7%) and 16 PD or failure (26%). The respective results in pts on MP were: CR 2 (3%), NCR 4 (6%), VGPR 5 (8%), PR 13 (20%), MR 7 (11%), ORR 48% (p

Description: Abstract 3862 Poster Board III-798 Acute light chain (LC) induced renal failure (ARF) is a severe complication of progressive MM. Reversal of ARF can only be achieved by fast, substantial and continuous suppression of production of pathogenic LCs. Bortezomib is highly effective and well tolerated in myeloma patients (pts) with renal impairment, because its metabolism is independent of renal function. In this study we evaluated the efficacy of Bortezomib in combination with doxorubicin and dexamethasone (BDD) in restoring renal function and in achieving tumor control in pts with LC-induced renal failure. In total, 72 pts have been enrolled; 2 pts did not fulfil inclusion criteria, 2 pts had been excluded because kidney biopsy revealed renal amyloidosis as main cause of renal failure. Hence, 68 pts constituted the intent to treat population and 58 pts were evaluable per protocol (≥2 cycles of therapy). Age: median 65.8; range 41-79 years. Forty-six (79%) pts presented with de novo MM, and 12 (21%) with progressive, previously treated disease; median baseline GFR was 20.0 ml/min (range 3.7-49.5 ml/min). ARF was defined as decrease in GFR to 100%, from

Description: Acute light chain induced renal failure (ARF) is a severe complication of progressive MM, leading to permanent renal dysfunction and dependence on chronic hemodialysis in a substantial proportion of patients (pts). Reversal of kidney failure can only be achieved by fast and substantial suppression of pathogenic light-chains with effective anti-MM therapy. Bortezomib in combination with doxorubicin and dexamethasone has been shown to be highly effective in newly diagnosed pts. In addition, bortezomib is well tolerated in pts with reduced glomerular filtration rate (GFR) and its half life is independent of renal function. In this study we aimed to evaluate the efficacy of the BDD regimen in restoring renal function and in achieving tumor control in pts with light chain-induced renal failure. Up to now 67 of 70 planned pts have been enrolled. Documentation is available for 55 pts for intent to treat analysis and for 47 evaluable for renal and tumor response (age: median 66 years, range 41–79 years, ISS stage I: 2%, II: 13%, III: 85%. 37 (79%) of pts presented with de novo MM, and 10 (21%) with progressive disease; baseline median GFR 19.8 ml/min (range 3.7–49.9ml/min). ARF was defined in newly diagnosed pts as reduction of GFR to 25% to

Description: Acute renal failure (ARF) is a severe complication of MM often leading to permanent renal dysfunction and dependence on chronic hemodialysis. Reversal of kidney failure can only be achieved by fast and substantial suppression of pathogenic light-chains by effective anti-MM therapy. In a previous pilot study we were able to reverse renal impairment with bortezomib based therapy in 5 of 9 pts (Haematologica 2007). Here, we present preliminary data from an ongoing phase II study in pts with ARF using the BDD regimen. Up to now 37 pts with MM induced ARF (age: median 64 yrs, range 41–82 yrs, DS stage I: 13%, II: 10%, III: 77%; IgGλ: 18%, IgGκ: 23%; Light chainκ: 32%, Light chainλ: 27%) have been enrolled. Seventeen (46%) pts presented with de novo MM, and 20 with progressive disease. ARF was defined as reduction of GFR to 25% and to 60ml/min within the last 4 weeks and with signs of tumor progression. Treatment regimen: Bortezomib 1.0mg/m2, d1,4,8,11, doxorubicin 9mg/m2, d1,4,8,11 until first safety analysis after enrollment of the first 5 pts and thereafter of 9mg2, d1,4, and dexamethasone 40mg d1,4,8,11. Cycles were repeated every 21 days. 22 pts have completed at least 3 cycles and are evaluable for response as yet. Overall response rate was 73% including 8 pts achieving CR, 4 nCR, 4 PR; 3 pts achieved MR. Median GFR at baseline was 17ml/min (range: 4 – 45ml/min) and improved to 45,5 ml/min (range: 11 – 134ml/min). A significant increase in GFR (〉75ml/min) was achieved in 9 of the 16 pts with CR-PR while in pts with MR or NC/PD no improvement in GFR was seen. Toxicity was assessed in 25 pts including 3 pts not evaluable for response. Grade 1–2 toxicities (〉10% of pts): anemia 40%, neutropenia 23%, thrombopenia 27%, fatigue 50%, infections/fever 64%, neuropathy 36%, edema 32%; diarrhea 27%, nausea 27%, mucositis 23%; Grade 3–4 toxicities: anemia 9%, neutropenia 23%, thrombopenia 9%, infections 18%, neuropathy 1%. Three of the infectious complications were due to herpes virus infections/reactivations. Three pts died during the first treatment cycle; 2 pts from pneumonia (including 1 with sepsis) and 1 pt (age 81 yrs) from myocardial infarction. This led to an adaptation of the treatment regimen including a reduction in the frequency of doxorubicin administration to days 1 and 4 (instead of d1,4,8,11), abandonment of the planned dose increase of bortezomib (to 1.3mg/m2), and addition of mandatory antibacterial and antiviral prophylaxis. In conclusion, overall anti-myeloma response rate in the 22 evaluable pts was 73%, with 12 (54%) pts achieving CR/nCR; ARF could be reverted in 9 pts. (41% of total or 56% of pts. with CR-PR). After dose reduction of the initial regimen, treatment was well tolerated in this high-risk and often multimorbid patient population. Tumor response Number of Pts (evaluable: 22) GFR (ml/min) Baseline Best response CR/nCR 12 18,2 (13–45) 62,5 (20–134) PR 4 25 (15–44) 81 (16–114) MR 3 17 (10–45) 35 (33–45) NC/PD 3 13 (4–15) 18 (11–25) CR-PR 16 GFR 〉75ml/min: 9 (56%)