ALBERT

Description: Abstract 2927 The standard of care for patients (pts) with asymptomatic multiple myeloma (MM) stage I/II or a stable response after chemotherapy is “watchful waiting”, with conventional agents failing to demonstrate benefits as early or maintenance therapy. We report data from a randomized, open-label, phase II study of BLP25 liposome vaccine (L-BLP25, Stimuvax®), a therapeutic cancer vaccine (TCV) targeting the mucin 1 (MUC1) antigen, in pts with previously untreated, slowly progressive, asymptomatic MM I/II or MM II/III in stable response/plateau phase following anti-tumor therapy. Pts were randomized to L-BLP25 and either a single (Group [Gp] A) or multiple (Gp B) low dose(s) of cyclophosphamide (CP). In both Gps, L-BLP25 (930 μg) was administered weekly for 8 wk, followed by maintenance vaccination every 6 wk until disease progression requiring anti-tumor therapy. A single dose of CP (300 mg/m2, maximum total dose 600 mg) was given 3 days before the first L-BLP25 dose and, in Gp B, also prior to the vaccination at wk 5 and each maintenance phase vaccination. The primary objective was to investigate the immune response to L-BLP25. A specific induced immune response to MUC1 was defined as ≥2-fold increase over baseline and no peptide control in an IFN- γ ELISpot, lymphoproliferation or intracellular IFN- γ FACS assay following short-term in vitro stimulation of PBMCs with MUC1-derived peptides, on ≥2 assessments. Secondary objectives included safety/tolerability, quality of the immune response, linkage of immune response to HLA restriction, clinical effects, time to progression and time to anti-tumor therapy. Median data are presented. Thirty-four pts (age: 64 years; 15 male) were randomized and received treatment (Safety Analysis [SA] set; A/B = 17/17) of which 32 (17/15) pts met the pre-specified criteria for immunologic analysis (Immunological Diagnostic Analysis [IDA] set). The duration of MM (SA set) was 34 vs 37 months (Gp A vs B) at study entry. The proportion of pts with untreated stage I/II vs previously treated stage II/III MM was 29 vs 71% (Gp A) and 47 vs 53% (Gp B). Of the previously treated pts, 83% (Gp A) and 100% (Gp B) had received high-dose chemotherapy with autologous stem cell transplantation. In this analysis, all pts had reached ≥50 wk or had discontinued study treatment. Treatment duration was 54 vs 87 wk (Gp A vs B), with 15 vs 21 L-BLP25 vaccinations and 1 vs 11 CP infusions (SA set). Cumulative CP dose (first 50 wk) was 297 vs 1769 mg/m2 (Gp A vs B), corresponding to a relative dose intensity of 100 and 97%. As in previous studies, spontaneously induced specific MUC1 immune responses were seen frequently pre-vaccination (baseline Gp A/B = 59/47%). Specific induction/augmentation of the MUC1 response was seen in 53% of pts following L-BLP25 treatment with no difference between Gps A and B. Rates of induction/augmentation following vaccination were similar for pts with vs without a spontaneous (pre-vaccination) immune response. First immune responses occurred early (≤9 wk) in the course of treatment. Assessments of cytokines will be presented. Objective clinical responses (Bladé criteria) were not seen, and were not anticipated given the aim of TCVs is to stabilize disease rather than induce a response according to established chemotherapy criteria. In a preliminary analysis, reduction in the slope of on-study M-protein concentration over time compared with pre-study data was seen in 13 of 30 pts (10/13 previously untreated and 3/17 previously treated; updated analysis will be presented). There was no association between presence of a treatment-induced MUC1 response and on-study changes in M-protein (area under the curve at wk 26 [AUC26]; IDA set). However, on-study M-protein AUC26 was significantly lower in pts without vs with a spontaneous pre-vaccination MUC1 response (pooled data for both groups: AUC26 = -5.2 [n=13] vs 16.2 [n=16], p=0.015). However, these data should be interpreted with caution given the small number of pts. Treatment was generally well tolerated. One possibly treatment-related fatal event of encephalitis occurred in Gp B. In summary, L-BLP25 led to MUC1-specific immune responses in a large proportion of MM pts and was associated with emerging clinical effects on M-protein concentration over time. Our data suggest that pts with previously untreated, early-stage disease may be the most likely to benefit from L-BLP25 vaccination. Further investigation of L-BLP25 in MM is warranted. Disclosures: Off Label Use: The abstract reports the results of a Phase II investigative study of L-BLP25 in multiple myeloma. L-BLP25 is a therapeutic cancer vaccine targeting mucin 1, which is widely expressed on common cancers. Österborg:Merck GmbH: Research Funding. Forssmann:Merck Serono S.A., 9 Chemin des Mines, CH-1202 Geneva, Switzerland: Employment. Senger:Merck KGaA, Darmstadt, Germany: Employment. Schröder:Merck KGaA, Darmstadt, Germany: Employment. Mellstedt:Merck-Serono: Honoraria, Research Funding.

Description: Abstract 2805 CHOP – based chemotherapy for aggressive lymphomas in patients with age-adjusted International Prognostic Index (IPI) score of 2–3 resulted in a historical 3-year progression free survival of approximately 30% in a previous Nordic phase III study. The aim of the present study is to determine whether an intensified regimen with chemoimmunotherapy and CNS prophylaxis improves outcome. Methods: From October 2004 to June 2008 patients were included in a phase II study. Inclusion criteria: 1) Age 18–65 years. 2) Newly diagnosed de novo diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) grade III. 3) No clinical sign of CNS disease and negative CSF cytology/flow cytometry by lumbar puncture. 4) No HIV infection. 5) WHO performance score 0–3. 6) Adequate organ functions. Schedule: Six courses of R-CHOEP14. Pegfilgrastim 6 mg sc. day four of each cycle. One course of high dose cytarabine 12 g/m2 (6 g/m2 for patients 60–65 years). One course of high dose methtrexate 3 g/m2 (1 g/m2 for patients 60–65 years). Biopsy and/or 18FDG PET/CT imaging of residual masses after fulfilled therapy was recommended, but not mandatory. Radiotherapy was given to residual masses of uncertain significance. Results. Demographic data:.156 eligible patients were included (97 males). Median age: 54 years (range 20–64). Histology: DLBCL: 145, FL grade 3: 12 (three patients no data). Age adjusted IPI score: 2: 117; 3: 39. Stage III-IV: 150 patients. LDH elevated: 151 patients. Performance status 2–3: 51 patients. B-symptoms were registered in 97 patients, more than one extranodal site in 42 and bulky lesions (≥ 10 cm) in 68. Median observation time for patients alive at last follow up was 36 months. Toxicity: Three toxic deaths are registered, one large bowel perforation, one fulminant hepatic necrosis and one septic shock. Hematological toxicity grade 4 was seen in 78% of the patients, infection grade 4 in 8%. Radiotherapy was given to 16% of the patients. Response: Response rates at end of therapy: CR/CRu: 69%, PR: 22%, SD: 1%, PD: 4.5%. Seventeen patients (7%) were not treated according to protocol, either due to lack of response (6 patients) or due to toxicity (eleven patients). The majority of the PR patients were considered to have residual masses and not viable tumour tissue. Survival: Three year overall survival was 80% (95% CI +/− 6.5%) and three year treatment failure free time 67% (95% CI +/−8.0%). CNS events: Seven patients had a CNS relapse, all but one were isolated (4 intracerebral, 3 meningeal). All CNS relapses occurred within 6 months after inclusion. Conclusions: The results are promising with a low three year treatment failure rate, a low toxic death rate and fewer CNS events than expected. The CNS events might be further reduced by earlier CNS prophylaxis. The study was supported by an unrestricted grant from Amgen Disclosures: Holte: Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. LeppÃ: Roche: Honoraria. Bjorkholm:Roche: Research Funding. Jyrkkiö:Roche: Honoraria. Kolstad:Roche: Honoraria; Amgen: Honoraria. Fosså:Roche: Honoraria. φstenstad:Roche: Honoraria; Amgen: Honoraria. Eriksson:Amgen: Research Funding.

Description: CHOP – based chemotherapy for aggressive lymphomas in patients with age-adjusted International Prognostic Index (IPI) score of 2–3 resulted in a historical 3-year progression free survival of approximately 30% in a previous Nordic phase III study. The aim of the present study is to determine whether an intensified regimen with chemoimmunotherapy and CNS prophylaxis improves outcome. Methods. From October 2004-June 2008 patients in Norway, Finland, Sweden and Denmark were included in a phase II study. Inclusion criteria: Age 18–64 years, newly diagnosed de novo DLBCL or FL grade III, no clinical sign of CNS disease and negative CSF cytology/flow cytometry by lumbar puncture, HIV negative, WHO performance status grade 0–3, adequate organ functions. Schedule: Six courses of rituximab and CHOP with the addition of etoposide 100 mg/m2 day 1–3 by i.v. route given every 14 day. Pegfilgrastim 6 mg sc. day 4 of each cycle. One course of cytarabine 12 g/m2 (6 g/m2 for patients 60–64 years). One course of methotrexate 3 g/m2 (1.5 g/m2 for patients 60–64 years). Biopsy and/or 18FDG PET/CT exam. of residual masses after fulfilled therapy was recommended, but not mandatory. Radiotherapy was given to residual masses of uncertain significance. Results. Demographic data: 160 patients were included (99 males). Median age: 54 years (range 20–64). Histology: DLBCL: 148, FL grade 3: 12. Age adjusted IPI score: 2: 120; 3: 40. Stage 3–4: 154 patients. LDH elevated: 154 patients. Performance status 2–3: 53 patients. B-symptoms were registered in 40% of the patients, more than one extranodal site in 23%, and bulky lesions (≥ 10 cm) in 43%. Data on toxicity and response rates were registered for 127 patients by Aug. 1st 2008 after the end of therapy and will be available for all patients by Dec 1st. Toxicity: Two toxic deaths were registered, one after large bowel perforation and one after an acute toxic necrosis of the liver. Hematological toxicity grade 4 was seen in 78% of the patients, infection grade 4 in 8%. Seven patients (5.5%) had major protocol deviations due to toxicity. Response: Two of the patients were non-responders at evaluation after 3 courses and were taken off therapy. Radiotherapy was given to 25 patients (20%). Response rates at end of therapy: CR: 54 (43%), CRu: 38 (30%), PR: 27 (21%), SD: 1 (1%), PD: 7 (5%). The majority (23/27) of the PR patients were considered to have residual masses and not viable tumor tissue and were observed without further treatment. Conclusions: Preliminary data indicate a low rate of toxic deaths despite intensive therapy. Remission rates are highly satisfactory for this subgroup of patients. Data are too premature for survival analysis at this time point.

Description: Hydroxyurea (HU) is used in suppressing the bone marrow and producing fetal-like red blood cells (RBCs). These RBCs are large in size and may theoretically disturb the microcirculation. In five patients with myeloproliferative disorders (MPD), the RBC geometry and deformability were analyzed before and after 6 to 8 months of HU treatment. In untreated MPD, the RBC geometry and filterability was normal. After HU, the RBC membrane area increased 24% and the cell volume increased 39% (P 〈 .005). This change resulted in a 12% increase in the minimum cylindrical diameter (MCD). From a static bending model of initial deformation, the RBC diametrical cross-section had a significantly increased section modulus. However, this increase in profile stiffness was compensated for by its larger projected cell area and, thus, pressure load on the RBC corpuscle. The resulting resistance to initial deformation therefore remained unchanged after HU. These findings were tested experimentally; with 3-μm filter membranes, HU treatment caused a significant increase in flow resistance (P 〈 .02), in accordance with MCD. However, with 5-μm pores, no difference was seen, again in consonance with the theoretical findings of initial deformation. Because most capillaries are larger than 3 μm, we suggest that HU is acceptable from a perspective of cellular microrheology.

Description: Abstract 803 Background: Recent findings lend strong support to the contention that histone deacetylase inhibition may be an important epigenetic therapy in the treatment of patients with myeloproliferative neoplasms and emphasize the need to characterize the efficacy and safety of this novel class of cytoreductive agents. Aims: This study was a non-randomized, open-label phase II multicenter study with sixty-three patients (21 essential thrombocythaemia (ET), 42 polycythemia vera (PV)) included from 15 centers. The primary objective was to investigate, if vorinostat as monotherapy in patients with PV and ET was followed by a decline in clonal myeloproliferation as assessed by conventional disease activity parameters. Secondary objectives included assessment of adverse effects during treatment; changes in bone marrow morphology before and after treatment with vorinostat and to investigate whether treatment with vorinostat influences the JAK2 mutant allele burden as assessed by quantitative PCR. (qPCR) Results: Thirty-one patients (49%) were followed to the end of the intervention period. Eighty-one percent of these had a partial (n=20) – or complete (n=5) hematological response according to ELN criteria. Response rates were found to be independent of JAK-status in ET patients. (P=0.83). A tendency towards less favorable responses was observed among patients with 〉 1 previous therapies albeit statistically insignificant (P=0.11). For all but two patients, a clinicohematological response was not followed by a histological remission. The prevalence of splenomegaly was lowered from 48% to 24% (P=0.02). A statistically significant reduction of JAK2 mutant allele burden was observed (P=0.006). No JAK2 positive patients experienced a complete molecular response defined as undetectable JAK2V617F by qPCR. No significant correlation between severity of tumor allele burden at inclusion and a more pronounced molecular response to vorinostat was found using a Spearman correlation analysis (rho = 0.16, p = 0.3). The most commonly reported adverse effects (AEs) during the intervention period among patients who completed the protocol were fatigue and gastrointestinal (anorexia, nausea, vomiting, diarrhea, dryness of the mouth). Gastrointestinal symptoms were generally manageable. Seventy percent of included patients experienced hair loss. Seventeen percent experienced renal toxicity (3 pts. grade I, 1 pt. grade II) and 1 pt. (4%) liver toxicity of unknown grade, which resolved after withdrawal of vorinostat. Forty-three percent of included patients required at least one dose reduction due to AE′s. Forty patients (63 % of patients) discontinued study drug before end of study period due to adverse events (65%), unknown (17.5%), withdrawal of consent (7.5%), no response (2.5%), or progression to acute leukemia (7.5%). Response rates for patients who discontinued therapy, however, showed that approximately 50% of patients who discontinued experienced a clinicohematological response providing evidence that toxicity issues were of concern rather than lack of clinical effect. Conclusions: Vorinostat is effective in patients with ET and PV normalizing elevated leukocyte and platelet counts as well as providing a statistically significant reduction of the JAK2 mutant allele burden and splenomegaly. However, vorinostat was associated with a high dropout rate. Considering the heterogeneity and complexity of oncogenic events, involving both deregulated tyrosine kinase activity as well as epigenetic deregulation in MPN-pathogenesis combination therapy (eg. JAK1-2 inhibitors, DNA-hypomethylating agents, interferon-alpha2) may be more efficacious than single agent therapy. This strategy might also allow for dose reduction of single agents and accordingly a decrease in toxicity, which was the major limiting factor for patients adhering to treatment in the present study. Disclosures: No relevant conflicts of interest to declare.

Description: Hydroxyurea (HU) is used in suppressing the bone marrow and producing fetal-like red blood cells (RBCs). These RBCs are large in size and may theoretically disturb the microcirculation. In five patients with myeloproliferative disorders (MPD), the RBC geometry and deformability were analyzed before and after 6 to 8 months of HU treatment. In untreated MPD, the RBC geometry and filterability was normal. After HU, the RBC membrane area increased 24% and the cell volume increased 39% (P 〈 .005). This change resulted in a 12% increase in the minimum cylindrical diameter (MCD). From a static bending model of initial deformation, the RBC diametrical cross-section had a significantly increased section modulus. However, this increase in profile stiffness was compensated for by its larger projected cell area and, thus, pressure load on the RBC corpuscle. The resulting resistance to initial deformation therefore remained unchanged after HU. These findings were tested experimentally; with 3-μm filter membranes, HU treatment caused a significant increase in flow resistance (P 〈 .02), in accordance with MCD. However, with 5-μm pores, no difference was seen, again in consonance with the theoretical findings of initial deformation. Because most capillaries are larger than 3 μm, we suggest that HU is acceptable from a perspective of cellular microrheology.

Description: Treatment with erythropoietin (epo) may improve the anemia of myelodysplastic syndromes (MDS) in approximately 20% of patients. Previous studies have suggested that treatment with the combination of granulocyte colony-stimulating factor (G-CSF) and epo may increase this response rate. In the present phase II study, patients with MDS and anemia were randomized to treatment with G-CSF + epo according to one of two alternatives; arm A starting with G-CSF for 4 weeks followed by the combination for 12 weeks, and arm B starting with epo for 8 weeks followed by the combination for 10 weeks. Fifty evaluable patients (10 refractory anemia [RA], 13 refractory anemia with ring sideroblasts [RARS], and 27 refractory anemia with excess blasts [RAEB]) were included in the study, three were evaluable only for epo as monotherapy and 47 for the combined treatment. The overall response rate to G-CSF + epo was 38%, which is identical to that in our previous study. The response rates for patients with RA, RARS, and RAEB were 20%, 46%, and 37%, respectively. Response rates were identical in the two treatment groups indicating that an initial treatment with G-CSF was not neccessary for a response to the combination. Nine patients in arm B showed a response to the combined treatment, but only three of these responded to epo alone. This suggests a synergistic effect in vivo by G-CSF + epo. A long-term follow-up was made on 71 evaluable patients from both the present and the preceding Scandinavian study on G-CSF + epo. Median survival was 26 months, and the overall risk of leukemic transformation during a median follow-up of 43 months was 28%. Twenty patients entered long-term maintenance treatment and showed a median duration of response of 24 months.The international prognostic scoring system (IPSS) was effective to predict survival, leukemic transformation, and to a lesser extent, duration of response, but had no impact on primary response rates.