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BACKGROUND. The objective of this study was to compare the efficacy of 3 regimens, cladribine alone, cladribine and cyclophosphamide combination, or cyclophosphamide, vincristine, and prednisone combination in previously untreated patients with low-grade B-cell non-Hodgkin lymphoma (LGNHL). METHODS. For this 3-arm, phase 3 study, 197 patients were randomly allocated to receive 6 monthly courses of cladribine alone, cladribine and cyclophosphamide combination, or cyclophosphamide, vincristine, and prednisone combination. Patients for whom all clinical data were available and 162 patients who completed scheduled chemotherapy were analyzed for the endpoints of this study. RESULTS. Compared with cyclophosphamide, vincristine, and prednisone combination regimen, cladribine alone or cladribine and cyclophosphamide combination induced higher probability of overall response (odds ratio [OR] = 4.0; 95% confidence interval [CI], 1.7–9,3; P = .002, and OR = 8.5; 95% CI, 3.2–22.7; P < .0001, respectively), complete remission (OR = 5.8; 95% CI, 1.8–18.5; P = .003; and OR = 14; 95% CI, 4.4–44; P < .0001, respectively), progression-free survival (log-rank test P < .0001), but not overall survival. After incorporating the International Prognostic Index in multivariate analysis, treatment with cladribine-containing regimens remained an independent prognostic factor for progression-free survival (χ2 = 35.94; hazard ratio = 2.38; P < .0002). Incidences of infections were similar in the randomized groups, whereas cladribine and cyclophosphamide combination, but not cladribine alone, induced more frequent neutropenia, anemia, and thrombocytopenia compared with cyclophosphamide, vincristine, and prednisone combination (P < .05 for each). This resulted in a higher frequency of prolongation of intervals between cladribine and cyclophosphamide combination and cyclophosphamide, vincristine, and prednisone combination cycles (P < .05), but dose reductions due to hematological or other toxicity did not differ significantly in cladribine alone, cladribine and cyclophosphamide combination, and cyclophosphamide, vincristine, and prednisone combination groups. CONCLUSIONS. For patients with LGNHL, first-line cladribine alone or cladribine and cyclophosphamide combination regimens both provided similar treatment responses, acceptable toxicity, and better response rates than cyclophosphamide, vincristine, and prednisone combination. Cancer 2008. © 2008 American Cancer Society.

Purpose: The purpose of this study was to assess humoral response to influenza vaccine in patients (pts) with non-Hodgkin lymphoma (NHL) as compared to healthy subjects (ctrl). Patients and methods: In two epidemic seasons, 2003/2004 and 2004/2005, 163 pts and 92 ctrl were vaccinated. Antibody titers to hemagglutinin (HA) and neuraminidase (NA) were measured in serum samples collected before vaccination, and 1 and 6 months apart. Changes in antibody titers were assessed by comparing geometric mean titers (GMT), mean fold increases (MFI), and seroprotection and seroresponse rates to baseline values. Results: Pts vaccinated in 2003/2004 had, after 1 month, increase in GMT by a factor of 8.64–26.60 for antihemagglutinin antibodies (HI) and 6.93–12.66 for antineuraminidase antibodies (NI), as compared to factor of 9.12–24.41 for HI and 4.83–10.31 for NI in ctrl. At 1 month after vaccination, seroprotection and seroresponse rates were similar in both groups, ranging from 68.42 to 84.21% and 71.93 to 94.74% in NHL, and 66.67–82.22% and 62.22–86.67% in ctrl, respectively. Pts vaccinated in 2004/2005 had increase in the GMT by a factor of 38.76–41.49 for HI and 26.59–30.31 for NI, as compared to factor of 81.19–104.32 for HI and 52.16–54.52 for NI in ctrl. Seroprotection and seroresponse rates were lower in the former group, ranging from 62.11 to 65.26% and 74.47 to 77.66%, respectively. In both seasons, pts achieved titres of antibodies greater than the protective threshold, irrespective of the previous chemotherapy administration. Conclusions: The results indicate that influenza vaccination induces sufficient immune response in pts with NHL, irrespective of previous chemotherapy.

In this multicenter study, we assessed the use of palifermin (recombinant human-keratinocyte growth factor 1) in the prevention of oral mucositis (OM) and acute GvHD (aGvHD) induced by a hematopoietic stem cell transplant (HSCT). Fifty-three patients with hematological diseases received three doses of palifermin (60 mug/kg once daily i.v.) pre- and post-conditioning regimens (total six doses). A retrospective control group of 53 transplant patients received no palifermin. There was a significant reduction in the incidence of OM of WHO (World Health Organization) grades 1-4 (58 vs 94%, P

Introduction Evidence suggests that skin rash may be a surrogate marker for epidermal growth factor receptor (EGFR) inhibitor efficacy. In the PA.3 study, rash (grade ≥2) was predictive of longer survival with gemcitabine plus erlotinib. The phase II, open-label, multicentre, randomised, RACHEL (BO21128) dose-escalation study evaluated whether metastatic pancreatic cancer patients with grade 0/1 rash after 4 weeks of gemcitabine/erlotinib therapy derived benefit from increasing the erlotinib dose beyond the standard 100mg/day, and whether dose escalation could induce rash or increase rash severity. Methods Eligible patients had histologically/cytologically confirmed metastatic pancreatic cancer, no prior systemic therapy for metastatic disease, and performance status 0–1. After a 4-week run-in period of gemcitabine (1000mg/m2, once-weekly) plus erlotinib (100mg/day), patients meeting all eligibility criteria were randomised to gemcitabine (1000mg/m2, days 1, 8, 15, 4-weekly cycle) plus erlotinib (100mg/day) or to gemcitabine (same dose) plus erlotinib dose-escalation (150mg starting dose, increasing by 50mg every 2 weeks to 250mg/day maximum until development of grade 2 rash or other dose-limiting toxicity). Patients who developed grade ≥2 rash during run-in were not randomised and received standard gemcitabine/erlotinib. Primary endpoint: overall survival (OS) between randomised arms; secondary endpoints: progression-free survival (PFS), incidence of grade ≥2 rash, response rate and safety. Results Of 467 enrolled patients, 36 withdrew during run-in and were excluded from the study; 179 had grade 0/1 rash but were ineligible for randomisation; 106 developed grade ≥2 rash during run-in and received standard gemcitabine/erlotinib without randomisation; 146 were eligible for randomisation (75 to standard erlotinib and 71 to dose-escalation erlotinib). Dose-escalation induced grade ≥2 rash in 29 patients (41.4%) versus 7 patients (9.3%) with standard-dose, a difference of 32.1% (95% CI 18.0–46.2; p Conclusion The erlotinib dose-escalation strategy induced rash in 41% of patients, but was not associated with increased clinical benefit compared with the standard erlotinib dose of 100mg/day. Table 1 .

367 Background: The phase II trial was conducted in the population of incurable patients with refractory or relapsed GCT to evaluate the activity of sorafenib, an oral multitarget inhibitor of Raf kinase and the tyrosine kinases VEGFR-2 and PDGFR-alpha. Methods: Patients with progressive metastatic GCT received sorafenib monotherapy continuosly 400mg bid until progression of disease or unacceptable toxicity. Serum tumor markers (STM) were assessed every 4 weeks and imaging was performed every 12 weeks. Responses were assessed using RECIST; STM normalization was required for complete responses and partial responses required at least STM stabilization. STM-only declines were recorded as stable disease. Descriptive analysis of efficacy and tolerance was conducted. Results: 18 male patients with nonseminoma were included between 9/2008 and 6.2010. Pts received median 3 (range 3-4) prior chemotherapy treatments, 2 had received prior high-dose therapy. Median age was 35 (range 26-48), primary site was testicular in 16 and in 2 cases retroperitoneal. All patients had STM elevation before treatment. Median treatment duration was 83 days (31, 617), 12/18 patients were treated more than 2 cycles, 8 pts experienced some degree of STM decline with prolonged SD lasted more than 350 days in 3 pts. No partial or complete responses were observed. Drug related adverse events (AEs) were mainly grade 1 and 2; 55% of patients experienced diarrhea, 44% rash, 55% HFSR, 33% hypertension, 28% fatigue. Some G3 toxicity occurred: diarrhea in one pts, hypertension in one patient, HFSR in 2/18. 31% and 22% of pts required dose interruption and reduction respectively due to AEs. Conclusions: Sorafenib monotherapy was well tolerated but did not demonstrated significant activity in patients with highly refractory GCT, although there were some prolonged SD observed. Clinical trial information: NCT00772694.

A feasibility of hybrid cell vaccination performed in remission following a standard chemotherapy (CHT) is currently being studied in patients with indolent B cell lymphomas at our institution under approval of the Ethics Committee. Adequate samples of fresh tumor tissue were collected from 16 patients. Seven patients were vaccinated with irradiated lymphoma/dendritic cell (DC) hybrids, and whenever the amount of collected viable lymphoma cells was not sufficient to complete vaccination with the use of cell hybrids, booster injections were alternatively performed with the use autologous DCs pulsed with tumor lysate. Autologous lymphoma cells were electrofused with autologous and/or allogeneic DCs, depending on accessibility of autologous DCs. Monocyte-derived DCs were basically generated from the peripheral blood adherent cells stimulated with GM-CSF and IL-4, and if available, from the bone marrow (BM) adherent cells. If only possible, autologous DCs were also generated from the BM non-adherent cells or from a sample of leukapheresis product collected for transplantation cultured with GM-CSF, TNF-α, SCF and FLT3-L to induce differentiation of DC progenitors. DC hybrids and/or DCs preincubated with tumor lysate were administered to uninvolved lymph nodes under USG guidance. Four patients failed to achieve a complete remission after initial therapy and the vaccination was discontinued due to disease progression (after 2, 2, 6, and 5 cycles). Three patients were vaccinated during remission following CHT. At present - 16, 18, and 10 months after starting the immunization, and after 8, 9, and after 7 cycles of vaccination, one patient with mantle cell lymphoma (MCL) is symptomless with persistent bone marrow (BM) involvement, one patient with MCL presenting with IgM paraproteinemia is disease-free with residual BM involvement (Fig 1), and one patient with follicular lymphoma is disease-free. Cutaneous delayed type hypersensitivity (DTH) response to DC/lymphoma hybrids exceeded the response to DCs alone in 3 of 7 vaccinated patients, and interferon-γ producing CD8+ cells specific to autologous lymphoma cells were demonstrated in one patient. In another patient, cutaneous DTH reaction was accompanied by transient pruritus and swelling of the injected lymph node two days after the sixth booster injection. No other adverse reactions to vaccinations were observed. Vaccination using the DC/lymphoma hybrids appears feasible, safe, and capable of inducing lymphoma cell specific immune responses. Further evaluation of efficacy in terms of disease control is mandatory. Fig 1. Disease and treatment course of a representative case Fig 1. Disease and treatment course of a representative case

Background: The 5-yr survival rate is Aims: The Polish Lymphoma Research Group Trial (PLRG MCL1) assessed whether 90Y-Zevalin (Z) could consolidate the response achieved from FCM ± R and improve ORRs and time to progression (TTP). Methods: Thirty MCL pts (stage III–IV) not suitable for SCTs were enrolled in 8 PLRG centers: 13 pts were newly diagnosed, 7 pts had a PR after first-line therapy, and 10 pts were in first relapse. Tumor burden was reduced by induction therapy with 3–6 cycles of FCM ± R (375 mg/m2) in all pts and staged after the third and subsequent cycles to assess tumor regression. Pts were in CR (no palpable lymph nodes or measurable masses on CT) or PR (1500/mL, PLTs >100,000/mL, and no BM hypoplasia received Z consolidation, starting with 2 doses of 250 mg/m2 R on days 1 and 8, followed by Z (0.3 or 0.4 mCi/kg, based on initial PLT count; maximum dose 32 mCi). ORR (CR + PR) and hematologic toxicity were determined. Response was monitored at 6 wk, 3 mo, and 3-mo intervals for up to 2 yr to assess TTP. Results: To date, 29 pts were evaluated. Of the 13 newly diagnosed pts 2 were in CR after completing FCM and 10 achieved CR after Z consolidation. Five of the 7 pts treated at first PR achieved a CR after Z and 2 pts achieved a PR. For the 10 pts treated at first relapse, 5 shifted from a PR after FCM to a CR after Z, 1 shifted from a CRu to a CR, and 3 pts achieved a further PR after Z. However, 5 of these 10 pts relapsed and 1 died due to hemorrhagic stroke. Of the 17 pts who shifted from PR to CR after Z, 13 continue in CR 8–20 mo after Z and 3 continue in CR 1–4 mo after Z. Overall, 19 of 20 pts treated at diagnosis or first PR are alive. Responses were accompanied by neutro- and thrombocytopenias 4–5 wk after Z, lasting 3–21 wk. To date, 7 pts required G-CSF (mean 21.3 doses; range 5–60), and 14 pts received red blood cell (mean 5.1 units; range 1–18) and/or PLT (mean 4.2 units; range 1–24) transfusions. No pts developed life-threatening infections. Hematologic toxicity was less severe in pts who had received only 3 FCM cycles, compared with patients requiring 5–6 FCM cycles. Conclusions: Following Z consolidation, 22 of 29 pts achieved a CR and 17 of these 22 shifted from a PR after FCM ± R to a CR. Therefore, Z consolidation is a feasible approach for MCL patients; it might have curative potential for pts treated at diagnosis or at first PR and may afford palliation for relapsed cases. Hematologic toxicity from FCM-Z is significant, but manageable, and correlates with the number of FCM cycles. Survival with FCM-Z seems superior to that reported for R-CHOP×4-Z. FCM-Z may be the preferred therapeutic approach.

To comparatively assess first-line treatment with cladribine single (C) or in combination with cyclophosphamide (CC), and COP (cyclophosphamide, vincristine, prednisone) in low grade B-cell non-Hodgkin lymphoma (NHL), previously untreated patients (pts) with Ann Arbor stage II-IV were randomly allocated to receive 6 monthly courses of either C, CC, or COP. End points were treatment response, freedom from progression (FFP) and overall survival (OS), and tolerance. From June 1, 2000 to June 30, 2005, 196 pts were randomized in 17 centers. Of 153 pts for whom data is available, 55 (36%) were diagnosed as small lymphocytic, 11 lymphoplasmocytoid (7%), 37 marginal-zone (24%), 42 follicular (27.5%), and 8 not otherwise specified low grade B-cell NHL (5.5%). Randomization constituted comparable groups, including International Prognostic Index variables. Compared to C and CC, COP induced lower overall response rates (75%, 90%, 50%, χ2 =7.9 p

Bcl-2 and Bcl-6 protein expression has been reported to predict progression-free (PFS) and overall (OS) survival of patients with Diffuse Large B-cell Lymphoma (DLBCL) in retrospective and prospective clinical studies. Reports on Bcl-2 expression frequency and predictive value have been conflicting. In the current study, paraffin-embedded tissue specimens from 79 newly diagnosed DLBCL patients subsequently treated with CHOP-like chemotherapy without rituximab were studied retrospectively using immunohistochemistry to evaluate expected influence of Bcl-2 and Bcl-6 on clinical outcome. Bcl-2 and Bcl-6 positivity was defined as staining in any of lymphoma cells and it was demonstrated in 78% of Bcl-2 and 58% of Bcl-6 patients. Frequency of Bcl-2 protein expression in our study was much higher then reported by others. Combinations of possible positive/negative staining results: Bcl2+/Bcl6+, Bcl-2+/Bcl-6-, Bcl-2-/Bcl-6+, Bcl-2-/Bcl-6- were found in 46%, 33%, 13%, and 9% of cases, respectively. Complete remission (CR) after initial chemotherapy was achieved in 54 of 74 evaluable patients (73%) and 6 patients (8%) had progressive disease (PD). CR rate was higher and relapse and death rate was lower in patients with Bcl-6+ tumor irrespective of Bcl-2 status. In patients with Bcl-6 negative lymphoma CR rate was higher when Bcl-2 was positive, but relapse and death rate was not affected by Bcl-2. Median OS and PFS were not reached after 21.3 months of follow-up in this group of patients. In the analysis using multivariate proportional hazards regression model, advanced clinical stage (CS III and IV vs. CS I and II) was the only significant factor predicting OS (p 1 (p Figure Figure

The aim of this study was to assess humoral response to influenza vaccination in 47 patients with non-Hodgkin lymphoma (NHL) in comparison with 45 healthy individuals (age 12–76 years, median 41 years; 13 males and 32 females). Patients (age 36–82, median 60 years; 24 males and 23 females) consisted of two groups, previously treated with chemotherapy (group A, n=32) or untreated (group B, n=15). In autumn 2003, all subjects were vaccinated with influenza vaccine ([Isquo]influvac’, Solvay Pharmaceuticals B.V.). Antibody responses to influenza hemagglutinin and neuraminidase were determined in sera collected before and 1 month after vaccination by hemagglutination and neuraminidase inhibition tests. Statistical analysis was performed using the Mann-Whitney unpaired and Wilcoxon paired tests. After vaccination geometric mean antibody titers (GMTs) of antihemagglutinin (HI) antibodies significantly increased (p1:40, ranged from 0% to 9.4% in group A, 0% to 13.3% in group B and from 2.2% to 20% in the controls. After vaccination protection rates increased and ranged from 78.1% to 87.5%, 73.3% to 93.3% and 66.7% to 82.2%, respectively. Response rates, i.e. the number of subjects with at least 4-fold increase of HI antibody titers after vaccination, ranged from 59.4% to 84.4%, 73.3% to 86.7% and from 51.1% to 66.7%, respectively. In both study groups and in the controls, post-vaccination antineuraminidase (NI) antibody titers were higher (p

We assessed humoral response to influenza vaccination (vacc) in two consecutive seasons 2003/2004 and 2004/2005 in 123 NHL patients. In season 03/04 50 patients (29 previously treated with chemotherapy - group A03/04 and 21 not treated - group B03/04) and 73 patients in season 04/05: 34 treated - A04/05, 39 not treated - B04/05 were vaccinated with trivalent subunit influenza vaccine. Antibody responses to influenza hemagglutinin (HI) and neuraminidase (NI) were determined in sera collected before vacc, after 1 month and after 6 months. One month after vacc geometric mean antibody titers (GMTs) of antiHI antibodies significantly increased (p1:40, ranged from 3.4 to 10.3% in A03/04, 2.9-8.8% in A04/05, 0–4.6% in B03/04 and 0–5.1% in B04/05. After 1 month protection rates ranged from 78.1 to 87.5% in A03/04, 61.8–70.6% in A04/05, 73.3–93.3% in B03/04 and 66.7–74.4% in B04/05 and decreased after 6 months to 24.1–37.9% in A03/04, 32.4–35.3% in A04/05, 19–47.6% in B03/04 and 17.9–35.9% in B04/05. Response rates, i.e. the number of subjects with at least a 4-fold increase of antiHI antibody titers after vacc, ranged from 58.6–75.9% in A03/04, 50–67.6% in A04/05, 57.1–81% in B03/04 and 61.5–71.8% in B04/05. Six months after vacc it decreased to 17.2–34.5% in A03/04, 20.6–29.4% in A04/05, 19–38.1% in B03/04 and 15.4–33.3% in B04/05. In all patients’ groups, post-vacc antiNI GMTs were significantly higher (p

6612 Background: Influenza virus infection can lead to severe complications in patients with immunodeficiency. Vaccination has been proved as beneficial in high risk groups. Methods: In autumn 2003...