Prognosis Of Pts Research Articles

Neoadjuvant treatment with weekly high-dose 5-fluorouracil as a 24h-infusion, folinic acid (AIO regimen) and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer: Long-term results of a phase II trial

15083 Background: Only 15–20% of all patients (pts.) with colorectal liver metastases are suitable for primary surgical resection. Liver resection offers the only chance of cure for these pts. In 2003 Wein et al. (Oncology) published the first data of neoadjuvant therapy following curative resection of liver metastases after a short median follow up (23 months) within a phase II trial. Here we report on the long-term results (median follow up: 45,5 months). Methods: Prospective phase II trial; pts.: n=20; start: 1/1998; end of recruitment: 2/2000; neoadjuvant chemotherapy: oxaliplatin (Eloxatin, 85 mg/m2 i.v. as a 2h-infusion (inf.); d 1, 15, 29 qd 57) and FA (Rescuvolin, 500 mg/m2 i.v. as a 1h- to 2h-inf.; d 1, 8, 15, 22, 29, 36 qd 57) followed by 5-FU (2600 mg/m2 i.v. as a 24h-inf.; d 1, 8, 15, 22, 29, 36 qd 57). Results: Last date of evaluation: 31/5/2007; localisation of the primary tumor: colon: n=40%, rectum: n=60%; histology: adenocarcinoma: n=20; G1/G2/G3/G4: 0/17/3/0; median age: 62,5 years; men/women: 75%/25%; ECOG 0/1: 10/10; higher grade toxicity: diarrhea CTC toxicity grade 3: 30%, vomiting grade 3+4: 15%; response of the neoadjuvant chemotherapy: CR: 10%, PR: 90%; metastatic resection: R0: 80%, R2: 20%. Median survival of all pts. (n=20): 3,0 years; 5-year overall survival (n=20): 40%. Median survival of the pts. (n=16) with R0 resection: 4,8 years; 5-year overall survival of the R0 resected pts.: 50%; 5-year disease-free survival rate: 25%. Median disease-free time period: 20,9 months. Conclusions: The neoadjuvant treatment with weekly high-dose 5-FU in the form of a 24h-inf. combined with FA and Oxaliplatin has proved to be highly effective and well tolerated. Disease-free survival rates and median overall survival rates are promising. Additionally, the data of a phase III trial published by Nordlinger et al. (ASCO 2007) indicate that a perioperative chemotherapy treatment combined with a curative resection of metastases may improve the prognosis in pts. with primarily resectable liver metastases. No significant financial relationships to disclose.

Human papillomavirus (HPV) infection as a prognostic factor in patients with oropharyngeal squamous cell carcinoma treated in a prospective phase II clinical trial

6035 Background: HPV16 is associated with improved survival in a patient (pt) subset with head and neck squamous cell carcinoma (HNSCC). In cervical cancer models, HPV oncoproteins, E6 and E7, can induce VEGF and HIF-1 expression. The purpose of this study was to determine HPV status in HNSCC pts enrolled in a prospective single-institution phase II clinical trial, and assess its effect on clinical outcome, HIF-1α and VEGF expression. Methods: Pts had resectable, untreated stage III, IV HNSCC of oral cavity, oropharynx, hypopharynx, or larynx, and stage II cancer of base of tongue, hypopharynx, or larynx. Neoadjuvant chemotherapy (NCT) consisted of docetaxel 60 mg/m2, a 96-hour infusion of cisplatin 25mg/m2/d, 5-FU 700 mg/m2/d, and LV 500 mg/m2/d. Pts received up to 3 cycles. Responding pts had organ-sparing surgery, then adjuvant radiation or chemoradiation. HPV status was determined by conventional PCR in fresh frozen biopsy samples and Taqman PCR on formalin-fixed, paraffin-embedded tissue prior to treatment. HIF-1α, VEGF expression were assessed by IHC and quantitative real-time PCR (RT-PCR). Multivariate Cox proportional hazards regression analysis of time to disease progression or death was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for HPV+ status. Results: HPV16 was detected in 14 (13 were oropharyngeal tumors) of 24 evaluable cases. There were no significant differences in response rates after NCT (86% vs. 90%) in HPV+ and HPV- pts, respectively. After median follow-up of 52.9 months, there was a trend toward better progression-free (HR=0.15, 95% CI 0.002–12.54; p=0.06) and overall survival (HR=0.14, 95% CI 0.001–14.12; p=0.10) for HPV+ pts. There was no difference in VEGF protein expression, but in a subset of 13 fresh frozen samples, RT-PCR revealed significant increase in VEGF mRNA transcript levels in HPV+ tumors (p<0.01). No difference was seen for HIF-1α expression. Conclusion: HPV presence portended a better prognosis in pts with oropharyngeal SCC treated with multimodality treatment in a prospective clinical trial. The benefit did not reach statistical significance due to small pt number. The level of VEGF mRNA was up-regulated in HPV16+ tumors possibly by a HIF-1 independent manner. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis

Cause of death in patients with lower-risk myelodysplastic syndrome (MDS)

7096 Background: We have recently developed a risk model specific for patients (pts) with lower risk MDS (Leukemia; in press) that allows the identification of poor prognosis pts. The cause of death (COD) of these pts is not well understood and relevant in view of their median age and their comorbidities. Methods: We reviewed data from 619 deceased pts with low or intermediate-1 disease by IPSS at presentation to MDACC from 1977 to 2006. Autopsy, final progress note, physician letter, or death certificate were used to determine COD. Each COD was arranged into an organ system and stratified by decade. Chi-square analysis and Kaplan-Meier log rank testing were utilized to detect differences between decades. Results: Information to determine COD was only available in 276 pts (45%). The median age at presentation was 66 years (range 19–88). The median age at time of death was 67 years (range 21–91). Overall median survival was 59 weeks (range = 1–831). An increase in median survival was noted from 1980 to 1990, 1990 to 2000, and 2000 to present (31, 57, and 79 weeks respectively, p = 0.004). A total of 88 pts (32%) transformed to AML prior to death, and the rate was stable over time (p = 0.654). By FAB classification, all subgroups were identified (RA = 114, RARS = 16, RAEB = 79, RAEB-t = 34, CMML = 33). By IPSS score, most pts were Intermediate-1 (Int-1 = 218 and Low = 58). Most pts had diploid cytogenetics (58.3%), and the most common cytogenetic abnormality was deletion of chromosome 5 (9.1%). Etiologies of infectious COD (p = 0.01) and renal COD (p = 0.003) declined over time, while hematological causes increased over each decade (p < 0.001). Other COD that were stable over time included cardiovascular, pulmonary, gastrointestinal, neurological, and oncologic causes. Sepsis (n = 40) and pneumonia (n = 39) were the most common infectious COD, but only pneumonia-related COD decreased over each decade (p = 0.003). MDS (n = 32) and AML (n = 29) were the primary hematological COD. Conclusions: This cohort of pts had a shorter median survival compared to historic controls, though median survival did improve with each decade. In addition, the most common COD has shifted over time, which may represent changes in practice. No significant financial relationships to disclose.

Clinical Impact of WT1 Mutations in the Context of Other Molecular Markers in Cytogenetically Normal Acute Myeloid Leukemia (AML): A Study of the German-Austrian AML Study Group (AMLSG).

Background: The Wilms' tumor 1 gene (WT1) encodes a zinc finger protein that functions as a transcriptional regulator. Although its role in haematopoiesis is still not clarified yet, disruption of WT1 function is discussed to promote stem cell proliferation and to induce a block in differentiation, the hallmarks of the two complementation groups of gene mutations that have been postulated for the development of acute myeloid leukemia (AML). In two small studies WT1 mutations were detected in 11% of cytogenetically normal (CN) AML and were associated with a lower complete remission (CR) rate and a higher rate of resistant disease (RD).Aims: To evaluate the incidence and clinical impact of WT1 mutations in the context of NPM1, FLT3-ITD (internal tandem duplication)/TKD (tyrosine kinase domain mutations at codon 835), CEBPA, MLL-PTD (partial tandem duplication), and NRAS mutation status in CN-AML.Methods: Bone marrow or peripheral blood samples from 279 younger adult patients (pts) 16 to 60 years of age with CN-AML (n=242 de novo, n=32 secondary, n=5 therapy-related) were studied. Pts had been entered on three AMLSG treatment trials (AML HD93, AML HD98A, AMLSG 07–04). WT1 gene mutation screening was performed using standard PCR-based direct sequencing of exons 1 to 10; mutation analyses for the other genes were performed as previously described.Results: WT1 mutations were identified in 37/279 (13%) CN-AMLs, predominantly clustering in exon 7 (25/37) and exon 9 (6/37), but also occurring in exons 1, 2, 3, and 8. Most of them were frameshift mutations resulting from insertions or deletions; 33 pts had heterozygous and 4 pts had homozygous mutations. Correlation of WT1 to the FLT3-ITD/TKD, NPM1, CEBPA, MLL-PTD, and NRAS mutation status revealed mutant (mut) WT1 to be significantly associated with FLT3-ITDpos (p=0.003) and CEBPAmut (p=0.02). In a multivariable logistic regression model on induction success, the genotype WT1mut was not significant (p=0.89); the only significant variable was the NPM1mut/FLT3-ITDneg genotype (p=0.003). In univariable analyses for overall (OS), event-free (EFS) and relapse-free (RFS) survival, there was no difference between the WT1wt and the WT1mut group. Multivariable Cox proportional hazard models for OS, EFS and RFS also revealed no significant impact of the genotype WT1mut (p=0.4, p=0.71, and p=0.81, respectively); significant variables were the genotypes NPM1mut/FLT3-ITDneg (p=0.007, p=0.0001, and p=0.01) and CEPBAmut (p=0.01, p=0.0003, and p=0.03); and in addition logarithm of white blood cell count for OS (p=0.02).Conclusion: In our study on a large series of molecularly well characterized CN-AML, WT1 mutations occurred in 13% of the pts and were significantly associated with the genotypes FLT3-ITDpos and CEBPAmut. However, in both univariable and multivariable analyses WT1 mutations did not impact on the prognosis of pts with CN-AML. Additional pts have to be investigated to determine whether WT1 mutation status might have an impact within distinct genotypes.

Abstract 3190: Gender Differences in Long-term Prognosis of Patients with Known or Suspected CAD and Severe LV Dysfunction Undergoing Gated Myocardial Perfusion SPECT

Objective : We aimed to assess the impact of gender on long-term prognosis in pts with known or suspected CAD and impaired vs. preserved left ventricular (LV) function assessed by means of gated myocardial perfusion SPECT (gSPECT). Methods . 575 consecutive pts (38% women, mean age 66±12 yrs;43% pharmacological stress) had rest/stress gSPECT and were then followed up for 11±1 yrs. 55 pts (9.6%) had severe LV dysfunction (post-stress LVEF≥35%). Follow-up end-point was all-cause death (ACD). Prognostic value of clinical and gSPECT variables in predicting ACD was assessed by multivariable Cox proportional hazards analysis. We also evaluated tested variables for presence of confounding and interactions. Results . During the follow-up, there were 143 ACD events (24.9%). Compared to men, women were younger, had less severe perfusion defects, higher LVEF, and smaller LV volumes. There was as a significant interaction between female gender and LV function; survival of women with LVEF≥35% was significantly worse compared to men with the same level of LV impairment, even after adjustment for all other significant predictors, such as age, perfusion defect extent/severity, abnormal ECG, rest HR, dyspnea, history of known CAD and diabetes. (Figure ; *p&lt;0.001). No difference found among the male and female pts with LVEF&gt;35%. Conclusion : In pts with severe LV dysfunction (within the so-called “AICD range”), female gender is associated with worse long term prognosis, independent of other prognostic markers and despite more favorable clinical profile. If confirmed in prospective studies, these findings may have important clinical implications in management of pts with severe LV impairment.

Response to primary chemotherapy (CHT) in advanced epithelial ovarian cancer (EOC) patients (pts) and molecular characterization of CHT-resistant tumor cell populations: Findings from the Arianna 02 Project

16059 Background: Despite a high response rate to CHT the prognosis of pts with advanced EOC remains poor. The molecular analysis of pre- and post-CHT tumor specimen may enable the identification of CHT resistant tumor cell populations and thereby lead to adapted treatment options. Methods: Stage III-IV EOC pts diagnosed by laparoscopy and biopsy and not suitable for optimal debulking surgery were eligible. Gene-expression profiles generated from total RNA using the Affymetrix U133A oligonucleotide microarray containing over 22,000 probe sets were obtained at diagnosis and on surgical specimens after 6 courses of primary carboplatin/paclitaxel CHT. Initial comparative analysis focused on proliferative and invasive tumor activity, and on growth factor- and hormone receptors expression. Results: 30 pts were enrolled and data were analyzed according to response to CHT and to time to relapse after surgery. Initial expression analysis results reveal that the quantitative determination of growth factor- and hormone receptors in pre- and post-treatment samples can be used to discriminate responders from non-responders and relates to clinical outcome. Moreover, multiple CHT-resistant tumor cell populations displayed pronounced estrogen receptor expression suggesting a role of hormone receptors in the development of CHT resistance. Conclusions: While hormonal therapies are used in the treatment of other endocrine related tumors, they are not approved for the treatment of EOC. Treatment of EOC cell lines with estrogens down-regulates GnRH activity and promotes cell growth, while tamoxifen has an opposite effect. However, further biological data are lacking in this setting and only few clinical trials have addressed this possibility so far. We have found that the expression of hormone receptors in vivo persists in CHT-resistant tumor cell populations after CHT for EOC. We suggest that hormone receptor activity contributes to the initial development of CHT resistance; hence endocrine therapies particularly in an early setting may be advantageous to a subset of pts and are worth studying. No significant financial relationships to disclose.

Rituximab, gemcitabine, vinorelbine, and methylprednisone (R-GVM), a hematopoietic cell (HC) mobilizing and salvage regimen for malignant lymphoma (ML)

17537 Background: The prognosis of pts with recurrent ML remains poor. High-dose therapy (HDT) with HC rescue can cure a proportion of such pts. HC mobilization can be adversely affected by number and duration of prior treatments, interval from diagnosis to HC collection, prior radiotherapy and marrow involvement. There remains a need for more effective and less toxic salvage regimens, capable of mobilizing HCs. Methods: The mobilizing potential of R-GVM salvage regimen with hematopoietic growth factor (HGF) support (G- and GM-CSF) was evaluated in 6 pts with relapsed (n=5) or primary refractory (n=1) ML. Pts received R-GVM salvage therapy [rituximab (375 mg/m2, day 1), gemcitabine (1 g/m2, day 1, 8), vinorelbine (30 mg/m2, day 1, 8) and methylprednisone (1 g/m2, day 1, 8)] with HGF administration and subsequent HC collection. The HGF support was started on day 9 and was continued through apheresis which started when the CD34+ cell count ≥ 20/μl (median day of R-GVM cycle: 15, range 14–19). Pts had daily apheresis with continued HGF support until at least 5 x 106 CD34+ cells/kg were collected. The hematologic and non-hematologic toxicity were tolerable in all pts; no pt required hospitalization. Results: 6 pts (age range 20–45 years) with Hodgkin (n =3) and non- Hodgkin lymphoma (n =3) were evaluated in this study. Pts had received 1–3 previous treatment regimens. The median number of R-GVM courses given before HC collection was 2.5 (range 1–5). Effective HC mobilization (≥5x106 CD34+ cells/kg) was obtained in all ps. A single apheresis resulted in satisfactory HC collection in 4 pts (range 8.2–17.7 x 106 CD34+ cells/kg); 2 pts required 3 aphereses to collect an adequate number of cells (6.7 and 7.4 x 106 CD34+ cells/kg). One pt was heavily pretreated and had failed two previous attempts of HC mobilization (one with HGF alone and one with cyclophosphamide and HGF); the other pt was HIV+ treated with HAART and had prior marrow involvement. As a salvage regimen, one pt had progressive disease, 1 had stable disease, 1 had a partial response, and 3 had a complete response before proceeding with HDT with HC rescue. Conclusions: R-GVM regimen is feasible, tolerable and effective in mobilizing HPC in patients with relapsed and refractory lymphoma. No significant financial relationships to disclose.

The Impact of Disease Status on the Outcome of High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT) for Peripheral T-Cell Lymphoma (PTCL).

The majority of patients (pts) with PTCL present with advanced stage with high-intermediate or high-risk IPI and their prognosis are poor with current standard induction chemotherapy. HDT followed by ASCT has been shown to be effective therapy for relapsed and refractory PTCL, although the outcomes of transplant varied depending upon the histologic subtype, disease status and IPI at transplant. Given the poor outcome with current treatment approach, HDT and ASCT as consolidative therapy during first remission are being investigated in pts with PTCL. We performed retrospective analysis of all pts with T-cell, NK cell and null cell lymphomas who underwent HDT and ASCT between 2/1991 to 6/2005. We analyze the outcome based on disease status at transplant and the subset of PTCL. There were 57 pts (35 male, 22 female) with a median age of 45 years (range 5–68). Histology included 6 (10.5%) angioimmunoblastic T-cell lymphoma (AILD), 26(46%) Anaplastic large cell lymphoma (ALCL), 22 (39%) PTCL, unspecified (NOS), 1 panniculitis like T-cell, 1 NK-T, and 1 adult T-cell lymphoma. Twelve (21%) were transplanted during first remission; 11 were high intermediate-high risk IPI, and 1 for histology NK-T. Twenty-eight (49%) were transplanted during relapse or ≥second remission and 17 (30% ) induction failure or primary refractory disease. Twenty-one (37%) had advanced stage III-IV at transplant. The median number of chemotherapy regimens was 2 (range 1–5). For ALCL subtype, 9 were anaplastic lymphoma kinase (ALK) positive, 9 ALK negative, 8 unknown.Results: At a median follow-up of 22 months (range 0.5–179), 29 are alive in remission, 25 relapsed and 3 died from transplant related mortality. One patient developed therapy induced myelodysplasia at two years post ASCT and is alive in remission after allogeneic stem cell transplant. The 2 years overall survival (OS) and disease-free survival (DFS) for the whole group were 53% (95% CI 46–60), and 45% (95% CI 39–50), respectively. The OS and DFS were significantly better for pts. who were transplanted in first complete remission (Figure1). The 2-year OS and DFS were both 83% (95% CI 55–94) for pts. transplanted in first remission compared to 45% (95% CI 38–52%, p=0.03) and 35% (95% CI 30–40, p= 0.006), respectively for those transplanted beyond first remission. Univariate models showed that the risk of death and/or relapse was significantly less among the pts. transplanted in first complete remission (OS, DFS and time to relapse: p < 0.05). When compared the outcome among the 3 subtypes, AILD, ALCL and PTCL NOS, there were no significant differences in survival or relapse among the 3 groups.Conclusion: our results suggest that HDT and ASCT can improve prognosis and survival of pts. with PTCL. The outcome of ASCT is best when performed during first complete remission. The role of HDT and ASCT during first remission should be further investigated in larger multi-center studies. In contrast to other reports, the prognosis of pts. with ALCL is similar to other PTCLs. [Display omitted]

Denileukin Diftitox (Ontak™) Therapy for Patients with Systemic Mastocytosis.

Systemic mastocytosis (SM) is characterized by abnormal proliferation and accumulation of neoplastic mast cells in various tissues. Patients (pts) with SM are empirically treated with recombinant interferon-alpha (IFN-α) or cladribine when cytoreduction is required. However, treatment with these agents has been associated with poor response rates, poor tolerance, and/or short response duration, and the prognosis of pts with SM is unchanged. This underscores the urgent need of new therapeutic approaches. Atypical expression of CD25 (the alpha-subunit of the interleukin-2 [IL-2] receptor), on the membrane of neoplastic mast cells represents an attractive therapeutic target. Denileukin diftitox (Ontak™) is an engineered fusion protein containing the active domain of the diphtheria toxin and the full-length sequence of IL-2, thus targeting IL-2 receptor-expressing cells. Upon internalization, protein synthesis is inhibited and cytotoxicity ensues. We designed a pilot trial for SM pts that either had aggressive form, or indolent form with uncontrolled symptoms despite supportive care measures, in which Ontak™ was initially administered at 9 ∝g/kg/day intravenously on days 1 through 5 every 21 days. This dose was increased after 3 cycles to 18 ∝g/kg/day in pts with no response and no significant toxicity. Therapy was discontinued in pts who showed no response after 6 cycles. Response was evaluated following guidelines proposed by Valent et al. (Leuk Res. 25;603–625, 2001). Thus far, a total of 7 symptomatic pts have been treated, 5 with aggressive and 2 with indolent SM. Median age was 58 years (range, 41 to 65), time from diagnosis to Ontak™ therapy 64 mo (range, 1 to 158), Hb 11.8 gr/dL (range, 9.2 to 13), WBC 7.9 ×109/L, (range, 2.5 to 16.9), platelet count 275 ×109/L (range, 54 to 759), eosinophil 2.3% (range, 0% to 6.1%). Five patients were previously treated with imatinib mesylate and one with cladribine; one pt had not received any prior therapies. One pt, who had undergone splenectomy, had hepatomegaly and 1 other had splenomegaly prior to start of Ontak™ therapy. In all patients malignant mast cells expressed CD25. A total of 33 cycles were administered. The median number of cycles was 5.5 (range 3 to 6). No significant responses have been observed among 7 pts treated. No significant difference was found between pre- and post- Ontak™ therapy in the percentage of bone marrow mast cells, and only one patient had decreased serum tryptase level at the end of the therapy (by 33%). No responses in C-findings were noted in patients with aggressive disease. However, symptoms related to SM improved in 3 patients and were eliminated in one. Therapy with Ontak™ was well tolerated with all toxicities being grade 1–2, without any grade 3–4. In summary, therapy with Ontak™ is very well tolerated but has no appreciable activity in pts with SM at the dose and schedule used in this study.

Cladribine (2-CDA) Plus Sequential Rituximab in Newly Diagnosed Disseminated Extranodal Marginal Zone B-Cell Lymphomas. A Phase II Study.

Background: Multiple extranodal localizations, nodal spreading and bone marrow (BM) involvement have been associated with shorter overall and event-free survival in Extranodal Marginal Zone Lymphoma (EMZL). No optimal treatment has yet been defined and, in this setting, Rituximab has demonstrated only moderate single agent activity while the role of purine analogs is still controversial, although promising in terms of objective response rate. In order to verify a potential synergy of these agents we conducted a prospective phase II trial evaluating a sequential treatment with 2-CDA, a purine nucleoside analog with proapoptotic and cytotoxic activity on both proliferating and quiescent lymphoid cells, and Rituximab in patients (pts) with untreated disseminated EMZL.Patients and methods: Pts with histologically confirmed MZL, ECOG < 2 and Stage IV disease were enrolled. 2-CDA was administered at a dose of 0.12 mg/kg on 5 consecutive days as a 2-hour infusion, every 4 weeks for 6 courses on outpatient basis. Thereafter, 4 doses of Rituximab (375 mg/m2, i.v., every 2 weeks) were delivered. Prophylaxis with TMP-SMX was required and filgrastim introduced if grade 3–4 neutropenia had occurred. Responses were evaluated after the 4th course of 2-CDA and at the end of the entire program.Results: Twenty-three pts (median age 67 yrs; r 34–81) with advanced [multiple extranodal site (n=16), BM (n=15), distant/diffuse nodal involvement (n=14), orbit (n=8), multicentric skin (n=3), gastric (n=4), leukemic (n=2), lung and pleura (n=3), salivary glands (n=3), Waldeyer's ring (n= 1), breast (n=1)] EMZL were accrued. B symptoms were present in 4 pts, abnormal LDH in 6. No pts had been irradiated and only 2 had received surgical resection due to emergency (ileum) and diagnostic (lung) procedures. All pts completed treatment program and were evaluable for response. The median number of delivered courses of 2-CDA was 6 (r 3–6). The overall response rate was 91 % [after the 4th course: CR=4, CRu=11, PR=6; at the end of treatment (i.e. including Rituximab): CR= 18 (78%), PR=3 (13%)]. Interestingly, a histological CR was achieved in 13 out of 15 pts with BM involvement (81%). Only 2 pts, with B symptoms at presentation, had a therapeutical diversion at the 3rd and 4th course due to minor response and persisting symptomatic disease. Extrahematological toxicity was negligible. CTCAE Grade 3 and 4 neutropenia occurred in 9 and 5 (22%) pts, respectively and febrile neutropenia occurred in 6 pts (26%). Grade 4 Thrombocytopenia and lymphocytopenia developed in 4 (17%) and 3 (13%) patients, respectively. Delayed grade 3 leuko- and thrombocytopenia occurred two months after 2-CDA withdrawal in three pts and slowly recovered in the following 6–8 weeks. No late opportunistic infection, nor disease recurrence have to date occurred. Failure free survival was 86 % at median follow up of 18 months (range, 4–34).Conclusions: Our prospective study shows that 2-CDA plus sequential Rituximab represents an effective strategy for the upfront treatment of disseminated EMZL. It is feasible in outpatient setting, and associated with favorable early and late toxicity profiles. While a longer follow-up will assess its impact on disease natural history, our results show for the first time that 2-CDA plus sequential rituximab may achieve very high CR rates even in poor prognosis pts with extragastric and widespread EMZL.

Phase II study of neoadjuvant chemotherapy (NAC) with S-1 and cisplatin (CDDP) for patients (pts) with metastatic or locally unserectable gastric cancer (MGC)

4078 Background: To improve the poor prognosis of pts with MGC, we conducted a phase II study to evaluate the feasibility and efficacy of intensive NAC to enhance surgical respectability and survival. Methods: Eligible criteria included histologically proven metastatic or locally unserectable gastric adenocarcinoma and measurable or evaluable disease, PS 0–2 and sufficient organ functions. The primary endpoint was overall survival and the secondary endpoints were overall resonse rate (ORR) and toxicities. Since Oct. 2000, chemotherapy-naïve 120 pts with MGC have received S-1 (80 mg/m2 orally intake for 21 consecutive days) and CDDP (50 mg/m2 intravenous drip infusion on day 8) as NAC. Treatment was repeated every 5 weeks. The median administered courses were three (range: 1–7), and median follow up periods were 13.8 months. Results: The proportion of the duration as an outpatient- therapy was 86%. 77.5% of pts (93/120) went to surgical resection; 36 had distal gastrectomy and 57 had total gastrectomy. ORR was 62.5% (CR 1, PR 74), and 61.7%, 75.7%, 28.6% and 23.8% for primary lesion, metastatic lymph nodes, liver metastases and peritoneal metastasis, respectively. Toxicity (grade 3/4): neutropenia 7.5%, thrombocytopenia 6.7%, anemia 6.7%, anorexia 5.8%, nausea 2.5%; no treatment related death. Survival: median 23 months; 1 year 79%; 4 year 31% in all pts, and 42 months; 83%; 38% in pts with gastrectomy, respectively. In univariate analyses, overall survival (OS) was predicted by the responder, limited tumor location, H0, P0, but not by age, sex, histological type, gross type, T-factor, N-factor, or performance status. In multivariate analyses, H0, P0 and responder independently predicted OS. In pts with gastrectomy, H0, curative resection, PS0 and responder predicted OS. Conclusions: NAC with S-1 and CDDP was feasible and useful for pts with MGC and resulted in a promising survival rate. No significant financial relationships to disclose.

Diagnostic and prognostic significance of a t(1;19)(q10;p10) in patients (pts) with low-grade oligodendroglioma and astrocytoma: NCCTG 94–72–53

1505 Background: Combined deletion of chromosomes 1p and 19q is associated with improved prognosis in pts with anaplastic oligodendroglioma. We recently discovered that the combined deletion is mediated by a chromosome 1;19 translocation: t(1;19)(q10;p10). The prognostic significance of this alteration in pts with low-grade gliomas is not known. Methods: Paraffin-embedded tumor tissue was obtained from 134 pts enrolled in two NCCTG trials for newly-diagnosed low-grade glioma: 86–72–51: a randomized phase III trial of 50.4 Gy vs 64.8 Gy radiation therapy (RT) and 93–72–02: a phase II trial of PCV for 6 cycles followed by RT. Interphase fusion of a CEP1 probe and a BAC contig probe for 19p12 was used to detect the 1;19 translocation. Analysis of 1p and 19q deletions had been previously performed by FISH. Kaplan-Meier distributions of overall survival (OS) and progression-free survival (PFS) for pts whose tumors did or did not exhibit CEP1/19p12 fusion were compared using the Wilcoxon test. Results: Of 134 pts, CEP1/19p12 fusion testing was informative for 92. CEP1/19p12 fusion prevalence was 55% among 42 oligodendrogliomas, 47% among 30 mixed oligoastrocytomas, and 5% among 20 astrocytomas. 91% of gliomas with and 11% without 1p/19q deletion had CEP1/19p12 fusion (p&lt;0.0001, chi-square test). The frequency of the t(1;19) by tumor histology, as well as median and 5-year progression-free and overall survival are provided in the table . Conclusions: Our results strongly suggest that a t(1;19)(q10;p10) mediates the combined deletion of 1p and 19q in human gliomas. Like combined 1p and 19q deletion, the 1;19 translocation is associated with superior progression-free and overall survival in low-grade oligodendroglioma patients. FISH analysis of the t(1;19) will likely be a more sensitive and specific means to assess 1p and 19q status in patients with gliomas. (Supported in part by CA85799, CA108961 and NCCTG grants CA25224 and CA114740) [Table: see text] No significant financial relationships to disclose.

Impact of prognostic markers on outcomes in patients with advanced chronic lymphocytic leukemia treated with the regimen of fludarabine/rituximab plus oblimersen (Bcl-2 Antisense)

6609 Background: Bcl-2, an anti-apoptotic protein is associated with treatment resistance and poor prognosis in pts with chronic lymphocytic leukemia (CLL). Preclinical studies have shown that oblimersen (Obl) enhances apoptosis induced by fludarabine (Flu) and rituximab (Rit). Increased CR and nPR in a phase 3 study confirmed the clinical benefit of combining Obl with a standard Flu+cyclophosphamide regimen in relapsed or refractory CLL pts. Similarly, in a phase 2 study, we found encouraging clinical activity when Obl was added to Flu/Rit. Here we report on outcomes related to baseline prognostic markers. Methods: All patients received Flu+Rit+Obl. Pts received Obl 1.5mg/kg/d, d1–7 by continuous IV, Rit (125 mg/m2 on d4, 250 mg/m2 on d6), and Flu 25mg/m2/d, d6–8 in the 1st cycle, and Obl 3mg/kg/d and Rit 375mg/m2 on d5 only, plus Flu on d5–7 in later q28 d cycles. Baseline data were collected on baseline cytogenetics and expression of Zap-70 and CD38 expression. Results: In the initial cohort, 24 pts (19 PT, 5 UT) were treated. CD 38 over-expression, Zap-70 expression, and abnormal cytogenetics were common; normal karyotypes (NK) were observed in only 5 (3 UT, 2 PT) pts. Median number of Flu+Rit+Obl cycles was 6. Overall, 5/5 UT and 12/19 PT pts responded. Two molecular CRs were noted (by flow and IgVh gene analysis), including 1 UT (CD38+, NK) and 1 PT (13q deletion) that had been refractory to Flu+Rit+Obl. Three nPRs were noted (2 UT [both CD38 and Zap-70+; 1 trisomy 12; 1 NK], and 1 PT [13q deletion]). Two PRs were observed in pts refractory to Flu and Flu+Rit, respectively. Two PRs were observed in 2 pts with poor risk (11q-) cytogenetics. Overall, 8/10 CD38+ pts and 5/11 Zap-70+ pts responded. Conclusions: Flu+Rit+Obl is an active and tolerable regimen in CLL. Major responses were noted in Flu- and/or Rit-refractory pts. Activity is noted despite poor prognostic markers. Accrual is ongoing. Efficacy, safety, and Bcl-2 regulation data will be presented. [Table: see text] [Table: see text]

A meta-analysis of two randomized, double-blind, placebo-controlled, phase III studies in patients (pts) with metastatic colorectal cancer (mCRC) receiving FOLFOX4 and PTK/ZK to determine clinical benefit on progression-free survival (PFS) in high LDH pts

3529 Background: PTK/ZK is an oral, antiangiogenic inhibitor of tyrosine kinase signaling of all known vascular endothelial growth factor receptors (VEGFR). PTK/ZK in combination with FOLFOX4 has been investigated in first line (CONFIRM 1[C1]) and second line (CONFIRM 2 [C2]) mCRC pts. Methods: In both trials, pts were randomized to receive PTK/ZK or placebo. Since high LDH and poor performance status (PS) have been shown to indicate poor prognosis in mCRC, pts were stratified by baseline serum LDH (≤ or &gt; 1.5 X ULN) and PS (0, 1–2), yielding 4 strata per trial. Exploratory analysis of the high LDH strata in C1 indicated that these pts may derive the most benefit from PTK/ZK treatment. The purpose of this pre-planned meta-analysis of C1 and C2 is to determine whether the treatment effect of C1 and C2 are consistent. Results: Both trials showed strikingly similar results. High LDH pts comprise approximately 30% of the total pt population. PTK/ZK seems to have the same strong effect on PFS in high LDH pts in both 1st and 2nd line mCRC with a HR for PFS of 0.67 (p =0.010) for C1 and 0.63 (p &lt; 0.001) for C2 (N=250 and N=316, respectively). The safety profile of PTK/ZK was highly consistent. The most frequent grade 3/4 AEs attributable to PTK/ZK were hypertension, diarrhea, fatigue, nausea, vomiting and dizziness. Increases in AEs associated with antiangiogenic therapy such as bowel perforations and bleeding complications were not observed in the PTK/ZK arms of both trials. In the meta-analysis, PTK/ZK effect on PFS is moderate in the overall population (HR 0.85, p-value 0.005). In contrast, the effect on PFS is strong and clinically meaningful in the high LDH population (HR 0.65, p-value &lt; 0.001, N=566). Conclusion: This meta-analysis is the largest study of poor prognosis pts with high serum LDH in metastatic colorectal cancer. These data suggest that PTK/ZK significantly improves PFS in high LDH pts. Further evaluation of PTK/ZK in this pt population is planned. [Table: see text]

Brief duration rituximab(R)/chemotherapy (CNOP or CVP) followed by maintenance rituximab in elderly/poor performance status patients (pts) with diffuse large B-cell lymphoma (DLBCL): A phase II trial of the Minnie Pearl Cancer Research Network

7577 Background: R-CHOP is the standard first-line treatment for pts with DLBCL; however, some pts are poor candidates due to general debility, cardiac disease, or other medical problems. Maintenance R is not effective after full course R-CHOP chemotherapy for DLBCL (ECOG 4494), but improves outcome following CHOP alone. In this phase II trial, we evaluated short course R/chemotherapy, followed by maintenance R, in pts who were not candidates for full-course R-CHOP. Methods: Eligibility: previously untreated DLBCL; stage II-IV; ECOG PS 0–2; age ≥ 70 years or poor CHOP candidate; adequate kidney, liver, bone marrow function; no HIV infection; informed consent. Pts received 3 courses of R-CNOP (cyclophosphamide 500mg/m2, mitoxantrone 10mg/m2, vincristine 1.0mg/m2, prednisone 80mg PO days 1–5, rituximab 375mg/m2) followed by pegfilgrastim 6mg sq day 2, at 21-day intervals. Mitoxantrone was omitted for pts with EF &lt; 40%. Pts with response/stable disease after chemotherapy began maintenance R (375mg/m2 weekly × 4 doses, administered at 6-month intervals × 4 courses). Results: 31 pts entered this trial between 5/03 and 11/05. Clinical characteristics: median age, 78 years; ECOG PS 2, 45%; IPI 3–5, 79%. 27 pts (87%) have completed short course R-chemotherapy; 20 pts (65%) are currently receiving maintenance R. After completion of R-chemotherapy, 17 pts (63%) had responses (9 CR/CRu, 8 PR); 10 pts had stable disease/minor response. After median 16 month follow-up, 29 of 31 pts (94%) are progression-free; actuarial 2-year PFS is 90%. The 2-year overall survival is 74%. 4 pts have died (progressive lymphoma 2, intercurrent illnesses 2). Grade 3/4 toxicities: neutropenia 38%, other toxicities &lt; 10%, no treatment-related deaths. Conclusions: Short-course R-chemotherapy followed by maintenance R was active and well tolerated in a group of elderly, poor prognosis pts with DLBCL. In spite of modest CR/CRu rate; the 90% 2-year PFS suggests a role for maintenance R. If these findings persist with further followup, this approach is worthy of further study in this patient group. [Table: see text]

Outcome of Patients Progressing or Relapsing after Primary Treatment with Two Cycles of Chemotherapy and Radiotherapy for Early Stage (Favorable) Hodgkin's Disease.

Purpose: To evaluate treatment outcome of patients (pts) with early stage (favorable) Hodgkin's disease (HD) with disease progression or relapse after primary treatment with two cycles of polychemotherapy followed by radiotherapy.Patients & Methods: From 1994 to 2002 pts with early stage HD were enrolled in two trial generations (HD7/HD10) of the German Hodgkin Study Group (GHSG). HD7 randomized CS IA-IIB patients with no risk factors (RF) to extended field radiotherapy (EFRT) alone or to 2 cycles of ABVD and EFRT. The HD10 trial randomized CS IA-IIB pts (ø RF) to 2 or 4 cycles of ABVD and 20 or 30 Gy involved field RT (IFRT). Treatment outcome and prognostic factors (PF) in pts with progressive or relapsed disease after 2 x ABVD + EF RT (HD7 Arm B) or 2 x ABVD + IF RT (HD10 Arm C + D) were retrospectively analysed and compared to pts registered in our database with treatment failure after RT alone or after 4 or 8 cycles polychemotherapy as front-line therapy.Results: A total of 1831 pts with early stage HD were enclosed in HD 7 and HD 10. 915 pts were treated with two cycles of ABVD followed by EFRT in 316 patiens (HD7 Arm B) or IFRT in 599 pts (HD 10 Arm C+D). 35 patients had progressive (17%) or relapsed HD (83%). Pts characteristics at relapse: median age: 40 yrs (range 19–72 yrs); histology: MC 39%, NS 37%, LCRHD 9%, LPHD 9%, LD 3%, not classified 3%; stage: CS I 26%, CS II 43 %, III 20 %, CS IV 11 %; B symptoms 8%; anemia (m < 12.0 g/dl; f < 10.5 g/dl) 23%; outfield relapse 40%. At progress/relapse 29% were treated with BEACOPP escalated, 29 % with HDCT/ASCT, 20% with COPP-ABVD-like regimens, 14% with BEACOPP baseline, and 8% with salvage RT. At 58 months median follow-up FF2F and OS were 49% and 62%, respectively. According to our recently developed prognostic score for relapsed HD (PF: duration of first remission, stage at relapse and anemia at relapse) patients with 2 or more RF had a FF2F and OS of 15 and 18% compared to 67% and 82% for pts with 0 or 1 RF. FF2F and OS at 58 months were comparable for pts treated with HDCT/ASCT (FF2F: 70%, OS 81%) or BEACOPP escalated (FF2F 64%, OS 78%). In contrast, pts tretaed with COPP-ABVD like regimens (FF2F 30%, OS 43%) or BEACOPP baseline (FF2F 19%, OS 22%) did worse. Compared to pts receiving RT as front line therapy alone pts treated with 2 x ABVD had a poorer outcome (RT alone: FF2F 79%, OS 82%). The outcome of pts pretreated with 4 (intermediate stages) or 8 cycles (advanced stages) of polychemotherapy at first diagnosis did not differ significantly and was inferior to pts pretreated with 2 x ABVD + RT.Conclusion: Disease progression or relapse after primary tretament with 2 x ABVD followed by radiotherapy is a rare event. The prognosis of pts treated with 2 x ABVD is impaired compared to patients treated with front-line radiotherapy alone. Modern treatment regimens like BEACOPP escalated or HDCT/ASCT should be used to salvage patients relapsing after a brief chemotherapy course and RT for early stage (favorable) HD.

A Multicenter Prospective Randomized Study Testing Non-Inferiority of Thalidomide 100 mg/day as Compared with 400 mg/day in Patients with Refractory/Relapsed Multiple Myeloma: First Results of the Final Analysis of the IFM 01-02 Study.

Thalidomide (THAL) has been widely shown to be effective in pts with relapsed or refractory multiple myeloma (RRMM). In a study by Yakoub-Agha of 83 patients (Hematol J, 2000), a high incidence of THAL-related toxicity greater than grade II was observed, which was related to both the dose-intensity and cumulative doses of THAL. The mean daily-received dose of THAL in the intial 90-day treatment period, however, was not found to influence response, OS or EFS. Given the dose related toxicities and the uncertainty regarding the minimal effective dose of THAL, the IFM conducted a prospective randomized study (sponsored by Pharmion developpement) in order to compare the efficacy of THAL 100 mg/day with 400mg/day in pts with RRMM after at least 2 lines of prior therapy or 1 line in absence of alternative treament. The study design had been approved by the ethical committee of Lille University Hospital and all pts had given written informed consent. Given the poor prognosis of pts with RRMM and the fact that THAL effect is potentiated by dexamethasone, this combination was planned in the protocol in case of treatment failure at any time or stable disease after 3 months of THAL treatment, in both study arms. Decreasing the THAL dose was permitted in pts experiencing toxicity; however, no increase over the initial THAL dose was allowed. The primary end point was the 1-year OS. Assuming a median survival time of 12 months in patients receiving 400 mg/day, non-inferiority was defined in the protocol as a decrease of no more than 4 months with the 100 mg/day dose. Sample size per arm was calculated to be 160 to guarantee a power of 80% when using a one-sided test with type I error of 5%. Secondary endpoints were response rate, EFS, and safety. Quality of life based on ECOG performance status, bone pain, and use of morphine derivatives was also evaluated. An interim analysis was performed on Oct 29, 2003 after inclusion of half of pts. Based on survival and safety results, the independent review committee recommended on one hand the continuation of the study and on the other, the increase of the sample size per arm to 200. On Oct 8, 2004, 400 pts were enrolled (100 mg n=205; 400 mg n=195). The median age at the onset of THAL was 68 years (range, 35–88), and of these, 190 (48%) were male. The median time from first treatment of MM to the onset of THAL treatment was 31 months (IQR, 20–51). Prior treatment consisted of conventional chemotherapy alone (n=182), single autotransplant (n=92), tandem autotransplant and over (n=126). M-component isotype was IgG, IgA and light chain only in 248 (62%), 93 (23%) and 47 (12%) pts, respectively. The light chain was kappa in 264 pts (66%). A chromosome 13 deletion at band 13q14 in bone marrow plasma cells was found in 45% of 203 evaluable pts. The median (IQR) values for serum B2 microglobulin, creatinine, albumin, and CRP at enrolment were 3.7 mg/L (2.5–5.7), 10.0 mg/L (8.5–12.7), 40 g/L (36–44), and CRP 5 mg/L (3–12), respectively. Given that the first final analysis was planned 1 year after the enrolment of the last patient (Oct, 2005), results will be available at the meeting.

Long Term Observation of CML Patients after Imatinib Resistance Associated with BCR-ABL Mutations.

The major cause of imatinib resistance in CML patients (pts) is clonal selection of cells harboring mutations of the BCR-ABL tyrosine kinase associated with various degrees of insensitivity to the drug. Management and outcome of these pts have been a matter of debate. In particular, retrospective studies suggested a poor prognosis of pts with P-loop mutations, whilst others did not confirm this observation. We sought to determine the outcome of 121 CML pts (73 m, 48 f; median age 61 yrs, range 28–80) with BCR-ABL mutations detected by direct sequencing and associated with hematologic (n=105), cytogenetic (n=14), or molecular (n=2) resistance. Imatinib was commenced between 8/99 and 3/05 after a median of 33.1 mo (range 0–312.3) after diagnosis, the median exposure to the drug was 17.0 mo (0.9–55.4). Resistance occurred after 18.1 mo (0.9–55.4) in chronic phase (CP, n=63), 18.3 mo (5.1–52.8) in accelerated phase (AP, n=33), 11.4 mo (0.9–47.7) in myeloid blast crisis (BC, n=20), and 9.1 mo (1.8–45.6) in lymphoid BC (n=5). Resistance was associated with 41 different mutations leading to a change of 32 amino acids (aa) of the P-loop area (n=38), T315I (n=15), the activation loop (n=11), and other sites (n=74). 15 pts showed 2, 2 pts 3, and one patient 4 mutations in parallel. In addition, resistance was associated with a loss of 27 aa including the P-loop in 2 pts. ABL polymorphisms were detected in 3 pts (T315T, n=1; K247R, n=2). Median time until resistance was 12.1 mo (0.9–52.8) for pts with P-loop mutations, 11.5 mo (2.8–47.7) for T315I, 17.2 mo (5.0–35.5) for activation loop mutations, and 20.4 (2.0–55.4) for others. After hematologic resistance, imatinib therapy was continued for 3.5 mo (0–54.1). Dose was increased in 42 pts up to 800mg/d, which was associated with disease stabilization in 7, hematologic improvement in 4, and cytogenetic or molecular improvement in 2 cases. In 46 pts, imatinib was combined with other drugs, 33 received low dose cytarabine. After imatinib withdrawal, treatment was continued with hydroxyurea, n=53, cytarabine, n=32, and/or other cytostatic drugs. 10 pts underwent allogeneic stem cell transplantation (SCT), 5 of them died. Recently, 2nd generation tyrosine kinase inhibitors were administered to 35 pts (dasatinib, n=19, AMN107, n=15, both drugs, n=1). Censoring pts at the time of SCT or start of alternative tyrosine kinase inhibitors, overall survival after resistance was 29.7 mo (0–52.3). 38 pts died; of these, mutations were located in the P-loop, n=16, at T315, n=4, or at other sites, n=18. Median survival after hematologic resistance was 29.7 mo for pts with P-loop mutations, 13.0 mo for pts with T315I, and 33.5 mo for others (n.s.). Considering CP pts only, median survival in case of P-loop mutations was 35.8 mo and has not been reached for pts with T315I and others (n.s.). In advanced disease, median survival with P-loop mutations was 17.0 mo, for T315I 13.0 mo, and for others 29.5 mo (n.s.). In conclusion, this prospective analysis failed to reveal a significantly impaired survival of pts with P-loop mutations compared to others. There is, however, a trend for a survival disadvantage in pts harboring T315I. Outcome of CML pts with mutations associated with insensitivity to imatinib, in particular P-loop and T315I mutations can be improved by early detection of the mutation and rapid withdrawal of the drug.

Doubling Time of Soluble CD23 Is an Additional Prognostic Factor in ZAP 70 Positive CLL Patients.

Background: Chronic lymphocytic leukemia (CLL) is a disease with unpredictable natural history in stage A patients (pts). Recently, It has been demonstrated that ZAP-70 and IgVH mutational status are powerful biological prognostic factors and we previously reported that the doubling time of soluble CD23 (sCD23DT) is a prognostic factor for progression of disease in untreated stage A CLL. Therefore we prospectively evaluated ZAP-70 protein expression and IgVH mutational status in untreated stage A B-CLL pts and correlated these markers with sCD23DT.Methods: sCD23 level was evaluated by commercially available enzyme-linked immunosorbent assay (ELISA). ZAP-70 expression is determined in leukemic cells by flow cytometry, and positive expression was defined as >20% positive cells. When tests became available, ZAP-70 gene expression and IgVH mutational status were also evaluated in all pts included in the sCD23 study.Results: 47 pts with untreated stage A B-CLL are evaluable for the sCD23DT. ZAP-70 and mutational status were evaluated in 34pts. Median age was 62 (42–82) years. The median follow-up was 58 (16–129) months. The sCD23DT was clearly associated with progression to upper stages requiring a treatment: median time to progression was 25 Mos in pts with sCD23 DT inferior to one year comparing to 141 months in pts with sCD23 DT superior to one year (p<0.0001). Time to progression in the group of pts with positive ZAP-70 expression was 19.1 mos comparing to 86.1 mos in ZAP-70 negative group (p=0.0001) Time to progression to treatment for pts with unmutated IgVH was 15,9 mos and 86,1 mos for pts with mutated status (p<0.001). In the group of pts with ZAP-70 positive expression 6pts (67%) needed a treatment. Among ZAP-70+ and sCD23DT< 1 year pts, 100% (6/6) required a treatment. For pts with positive ZAP-70 and a sCD23DT superior to one year, 100% (3/3) of pts do not need a treatment (p=0.0188). In the group of good prognosis pts with negative ZAP-70, 24% (6/25) of the pts required a treatment, median time to progression for these pts was 66,6 mos. in the ZAP-70 negative pts population, 3/25 (12%) have a sCD23DT<1 year and 2 of these pts required a treatment for disease progression. Among the pts with indolent progression, negative ZAP-70 and who do not need a treatment, 96 % of the pts have a sCD23DT superior to one year. In the group of pts with unmutated status (n=8), 88% of the pts needed a treatment and all the pts had a sCD23DT inferior to one year, the only pts who did not required a treatment had a sCD23DT superior to one year. Among patients with mutated IgVH 73% did not require a treatment and 95% of those pts had a sCD23DT superior to one year. Among the mutated pts who progressed to treatment 42% had a sCD23DT inferior to one year, the 58% of treated pts with sCD23DT superior to one year and unmutated status had a median time to progression of 68 mos. In conclusion, CLL patients can be divided into different risk categories according to sCD23 serial determinations. sCD23DT is an additional important prognostic marker for disease progression even in ZAP-70 positive patients.

Juvenile idiopathic arthritis outcome and prognosis according to catamnesis evaluation

Objective. To study outcome and prognosis in pts with juvenile idiopathic arthritis (JIA). Material and methods. 239 JIA pts with disease duration of 10 years and more were analyzed. 80 children and adolescents before 18 years old (66 girls and 14 boys) were included in group 1. Arthritis clinical and laboratory activity, radiological stage and functional status according to Steinbroker and CHAQ questionnaire were assessed. 159 grown up pts (109 female and 50 male) suffering from JIA from childhood were included in group 2. They were examined using Stanford Health Assessment Questionnaire (HAQ) and a specially developed social status questionnaire. Results. Half pts of group 1 had recurrence of the disease during examination but activity in most cases did not exceed stage I or 2 (54% and 31% respectively). Joint destructive changes were revealed in 50% of pts. 80% of pts had radiological signs of secondary osteoarthritis. Amyloidosis was revealed in 2 from 27 pts with systemic type of JIA. 68% of pts had 1 or 2 functional class. 1/3 of pts did not have functional limitations (CHAQ=0). 13% of pts had maximal disability with CHAQ ranging from 2,1 to 3,0 (pts with polyarticular and systemic types of JIA. Most grown up pts (59%) considered their health as good. Substantial part of them worked or learned. 10 pts did not worked because of the disease (1,5%). 61% of pts did not have functional limitations (HAQ=0). 32% of pts were disabled. Most of them had 3 or 2 disability degree and had possibility to work. Conclusion. Substantial part of pts with longstanding JIA have stabilization of the disease or remission. Recurrent course of the disease was characterized by decrease of activity. Most children and grown ups with longstanding disease have relatively benign functional outcome. Pts with polyarticular and systemic types of JIA require especial attention because they have maximal risk of joint destruction with severe disability.