Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer.

OBJECTIVE: To evaluate the antitumor activity and safety profile of plitidepsin administered as a 1h weekly intravenous (i.v.) infusion of 3.2mg/m(2) to patients with small cell lung cancer (SCLC) who relapsed or progressed after one line of chemotherapy. PATIENTS AND METHODS: This was a multicenter, open-label, single-arm, exploratory, phase II clinical trial. Treatment lasted until disease progression, unacceptable toxicity, patient refusal or treatment delay for >2 weeks. Objective response rate (primary efficacy endpoint) was evaluated according to response evaluation criteria in solid tumors (RECIST). The rate of stable disease (SD) lasting for at least 6 months and time-to-event variables were secondary endpoints of efficacy. Toxicity was assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. RESULTS: Twenty pretreated SCLC patients (median age, 60 years) with extensive (n=13) or limited-stage disease (n=7) received a total of 24 treatment cycles (median, one cycle per patient; range, 1-2). Objective tumor responses were not observed and only one of the 17 evaluable patients had SD. With a median follow-up of 11.8 months, the progression-free survival and the median overall survival were 1.3 months and 4.8 months, respectively. The most troubling or common toxicities were fatigue, muscle weakness, lymphopenia, anemia (no patients showed neutropenia), and asymptomatic, non-cumulative increase of transaminases levels and alkaline phosphatase. CONCLUSION: This clinical trial shows that a cycle of 1h weekly i.v. infusion of plitidepsin (3.2mg/m(2)) was generally well tolerated other than fatigue and muscle weakness in patients with pretreated SCLC. One patient died due to multi-organ failure. The absence of antitumor activity found here precludes further studies of this plitidepsin schedule as second-line single-agent treatment of SCLC.

First-line temozolomide combined with bevacizumab in metastatic melanoma: a multicentre phase II trial (SAKK 50/07).

BACKGROUND: Oral temozolomide has shown similar efficacy to dacarbazine in phase III trials with median progression-free survival (PFS) of 2.1 months. Bevacizumab has an inhibitory effect on the proliferation of melanoma and sprouting endothelial cells. We evaluated the addition of bevacizumab to temozolomide to improve efficacy in stage IV melanoma. PATIENTS AND METHODS: Previously untreated metastatic melanoma patients with Eastern Cooperative Oncology Group performance status of two or more were treated with temozolomide 150 mg/m(2) days 1-7 orally and bevacizumab 10 mg/kg body weight i.v. day 1 every 2 weeks until disease progression or unacceptable toxicity. The primary end point was disease stabilisation rate [complete response (CR), partial response (PR) or stable disease (SD)] at week 12 (DSR12); secondary end points were best overall response, PFS, overall survival (OS) and adverse events. RESULTS: Sixty-two patients (median age 59 years) enrolled at nine Swiss centres. DSR12 was 52% (PR: 10 patients and SD: 22 patients). Confirmed overall response rate was 16.1% (CR: 1 patient and PR: 9 patients). Median PFS and OS were 4.2 and 9.6 months. OS (12.0 versus 9.2 months; P = 0.014) was higher in BRAF V600E wild-type patients. CONCLUSIONS: The primary end point was surpassed showing promising activity of this bevacizumab/temozolomide combination with a favourable toxicity profile. Response and OS were significantly higher in BRAF wild-type patients.

RTOG 0525: Exploratory Subset Analysis from a Randomized Phase III Trial Comparing Standard (std) Adjuvant Temozolomide (TMZ) with a Dose-dense (dd) Schedule for Glioblastoma (GBM)

Purpose/Objective(s): RTwith TMZ is the standard for GBM. dd TMZ causes prolongedMGMTdepletion in mononuclear cells and possibly in tumor. The RTOG 0525 trial (ASCO 2011) did not show an advantage from dd TMZ for survival or progression free survival. We conducted exploratory, hypothesis-generating subset analyses to detect possible benefit from dd TMZ.Materials/Methods: Patients were randomized to std (150-200 mg/m2 x 5 d) or dd TMZ (75-100 mg/m2 x 21 d) q 4 weeks for 6- 12 cycles. Eligibility included age.18, KPS$ 60, and. 1 cm2 tissue for prospective MGMTanalysis for stratification. Furtheranalyses were performed for all randomized patients (''intent-to-treat'', ITT), and for all patients starting protocol therapy (SPT). Subset analyses were performed by RPA class (III, IV, V), KPS (90-100, = 50,\50), resection (partial, total), gender (female, male), and neurologic dysfunction (nf = none, minor, moderate).Results: No significant difference was seen for median OS (16.6 vs. 14.9 months), or PFS (5.5 vs. 6.7 months, p = 0.06). MGMT methylation was linked to improved OS (21.2 vs. 14 months, p\0.0001), and PFS (8.7 vs. 5.7 months, p\0.0001). For the ITT (n = 833), there was no OS benefit from dd TMZ in any subset. Two subsets showed a PFS benefit for dd TMZ: RPA class III (6.2 vs. 12.6 months, HR 0.69, p = 0.03) and nf = minor (HR 0.77, p = 0.01). For RPA III, dd dramatically delayed progression, but post-progression dd patients died more quickly than std. A similar pattern for nf = minor was observed. For the SPT group (n = 714) there was neither PFS nor OS benefit for dd TMZ, overall. For RPA class III and nf = minor, there was a PFS benefit for dd TMZ (HR 0.73, p = 0.08; HR 0.77, p = 0.02). For nf = moderate subset, both ITT and SPT, the std arm showed superior OS (14.4 vs. 10.9 months) compared to dd, without improved PFS (HR 1.46, p = 0.03; and HR 1.74, p = 0.01. In terms of methylation status within this subset, there were more methylated patients in the std arm of the ITT subset (n = 159; 32 vs. 24%). For the SPT subset (n = 124), methylation status was similar between arms.Conclusions: This study did not demonstrate improved OS for dd TMZ for any subgroup, but for 2 highly functional subgroups, PFS was significantly increased. These data generate the testable hypothesis that intensive treatment may selectively improve disease control in those most likely able to tolerate dd therapy. Interpretation of this should be considered carefully due to small sample size, the process of multiple observations, and other confounders.Acknowledgment: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI).

Valor pronóstico de la densidad microvascular y de la expresión del VEGF, EGFR y HIF-1 en pacientes con cáncer de cérvix localmente avanzado tratados con quimioradiación

Introducción: Colombia cuenta con poca información sobre el comportamiento del cáncer, no obstante, el carcinoma de cuello uterino representa la segunda causa de muerte por la enfermedad entre las mujeres de nuestro entorno. El patrón epidemiológico de la enfermedad es preocupante porque los estados localmente avanzados constituyen el estado más frecuente al momento del diagnóstico y la mortalidad siendo bastante alta a pesar de la presencia de un programa de cribado organizado. Objetivo: Describir el valor pronóstico de la densidad microvascular (DMV) y de la expresión proteica de varios genes relacionados con la supervivencia y proliferación del cáncer de cérvix localmente avanzado en un grupo de mujeres tratadas con quimioradiación y braquiterapia intracavitaria. Se estimaron la tasa de respuesta global (TRG), la supervivencia libre de progresión (SLP) y la supervivencia global (SG). Resultados: Se incluyeron 61 mujeres con una edad media de 52 ± 10 años; todas tenían diagnóstico de cáncer de cérvix localmente avanzado (IIA 2.3%/IIB 47.5%/IIIA 4.9%/IIIB 37.7%/IVA 3.3%/no definido 3.3%), con un volumen tumoral promedio de 6.4cm (DE ± 1.8cm) e infección por VPH en 46% de los casos; 58 sujetos (95%) tenían un patrón escamoso, dos fueron adenocarcinomas y &50% presentaba neoplasias moderada o pobremente diferenciadas. Todas fueron tratadas con quimioradiación (interrupción transitoria en teleterapia por toxicidad y otras causas en 19% y 21.4%, respectivamente/media de ciclos de platino concomitante 4.8 series ± 1.0) y braquiterapia (77% completaron el tratamiento intracavitario). La mediana para la SLP y global fue de 6.6 meses (r, 4.0-9.1) y 30 meses (r, 11-48), respectivamente. Ninguna de las variables tuvo un efecto positivo sobre la SLP, mientras el análisis multivariado demostró que los niveles de expresión del VEGF (P=0.026), EGFR (P=0.030), y el volumen tumoral menor de 6 cm (P=0.02) influyeron positivamente sobre éste desenlace. Conclusión: Existe una influencia positiva sobre el pronóstico, de la tipificación en el cáncer de cérvix localmente avanzado tratado con quimioradiación basada en platino.

Response evaluation in third- and fourth-line treatment of GIST: the role of PET

Background: Response evaluation in gastrointestinal stromal tumors is difficult. Computed tomography and size-based assessments have been found inadequate to draw prognostic conclusions in patients treated with tyrosine kinase inhibitors (TKI). Density criteria (CHOI) have recently been shown to better define prognostic subsets of patients evaluated with CT. Still, positron emission tomography (PET) might be better at identifying responders with good outcome early, as shown for first and recently second-line treatment in GIST (Prior et al.; J Clin Oncol 2009). We wanted to evaluate the role of PET in third- and fourth-line TKI treatment of GIST. Methods: We retrospectively reviewed patients with GIST who had received third- or fourth-line treatment with TKI and had undergone PET for response evaluation. Patient needed to have a baseline and at least one subsequent PET. Results of the first "early" PET after treatment start have been used throughout this analysis and EORTC PET Study Group criteria applied. Results: Twelve treatment courses were evaluable, seven with Nilotinib in third- and five with Sorafenib in fourth-line treatment, in 8 patients, median age 60 y (range 36−78 y), who had all failed prior Imatinib and Sunitinib treatment due to disease progession. Baseline and follow-up PET were performed within a median of 34 days (range 9−84 days). Median progression-free survival (PFS) was 262 days in patients responding to PET versus 76 days in patients with stable or progressing disease (p = 0.15). Conclusions: This small series suggests that PET retains its value for outcome prediction in third- and fourth-line TKI treatment of GIST. This could be of particular clinical value in these vulnerable patients with large tumour masses. Early PET may help in stopping ineffective, but toxic therapy and help switching to a more effective therapy. PET should be evaluated further in this patient population.

Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial.

BACKGROUND: In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. PATIENTS AND METHODS: Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. RESULTS: Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. CONCLUSION: HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EUDRACT NUMBER AND CLINICALTRIALSGOV IDENTIFIER: 2004-002245-12 and NCT00110123.

Second cranio-facial malignancies in hereditary retinoblastoma survivors previously treated with radiation therapy: clinic and radiologic characteristics and survival outcomes.

INTRODUCTION: Hereditary retinoblastoma survivors have an increased risk for cranio-facial second primary tumours (SPT), especially after treatment with external beam radiotherapy (EBRT). This multicentre study evaluates the clinical and imaging characteristics and outcomes of cranio-facial SPTs in irradiated retinoblastoma survivors. PATIENTS AND METHODS: Clinical and radiological data of 42 hereditary retinoblastoma patients with 44 second and third malignancies were reviewed. Radiological data included anatomic location and computed tomography (CT) and magnetic resonance (MR) characteristics. Cox regression and likelihood ratio chi-square test were used to evaluate differences in patients' survival rates. RESULTS: Cranio-facial SPTs were diagnosed at a median age of 13 years. Histological types included osteosarcomas (43%), rhabdomyosarcomas (20%) (57% embryonal, 43% alveolar) and a variety of other types of SPT (37%). Predilection sites were: temporal fossa (39%), ethmoid sinus (23%), orbit (18%), maxillary sinus (16%) and intracranial dura mater (4%). Most of the osteosarcomas (78%) and rhabdomyosarcomas (80%) occurred in patients treated with EBRT in the first year-of-life. Treatment of SPTs with a microscopically complete surgical resection led to a significantly better 5-year overall survival (OS) (P=0.017) and event-free survival (EFS) (P=0.012) compared to patients treated without surgery or incomplete resection (OS: 83% versus 52%; EFS: 80% versus 47%). CONCLUSIONS: Osteosarcomas and rhabdomyosarcomas are the most common cranio-facial SPTs in irradiated hereditary retinoblastoma survivors, which develop in specific locations and occur predominantly in patients irradiated in their first year-of-life. Microscopically complete surgical resection of SPTs is a major prognostic factor, suggesting the potential benefit of early detection by imaging.

Autologous Stem Cell Transplantation (ASCT) for Enteropathy-Associated T-Cell Lymphoma (EATL): Final Analysis of a Retrospective Study On the Behalf of Lymphoma Working Party (LWP) of the European Group for Blood and Marrow Transplantation (EBMT).

Background: EATL is a rare subtype of peripheral T-cell lymphomas characterized by primarily intestinal localization and a frequent association with celiac disease. The prognosis is considered to be poor with conventional chemotherapy. Limited data is available on the efficacy of ASCT in this lymphoma subtype. Primary objective: was to study the outcome of ASCT as a consolidation or salvage strategy for EATL. The primary endpoint was overall survival (OS) and progression-free survival (PFS). Eligible patients were > 18 years who had received ASCT between 2000-2010 for EATL that was confirmed by review of written histopathology reports, and had sufficient information on disease history and follow-up available. The search strategy used the EBMT database to identify patients potentially fulfilling the eligibility criteria. An additional questionnaire was sent to individual transplant centres to confirm histological diagnosis (histopathology report or pathology review) as well as updated follow-up data. Patients and transplant characteristics were compared between groups using X2 test or Fisher's exact test for categorical variables and t-test or Mann-Whiney U-test for continuous variables. OS and PFS were estimated using the Kaplan-Meier product-limit estimate and compared by the log-rank test. Estimates for non-relapse mortality (NRM) and relapse or progression were calculated using cumulative incidence rates to accommodate competing risk and compared to Gray's test. Results: Altogether 138 patients were identified. Updated follow-up data was received from 74 patients (54 %) and histology report from 54 patients (39 %). In ten patients the diagnosis of EATL could not be adequately verified. Thus the final analysis included 44. There were 24 males and 20 females with a median age of 56 (35-72) years at the time of transplant. Twenty-five patients (57 %) had a history of celiac disease. Disease stage was I in nine patients (21 %), II in 14 patients (33 %) and IV in 19 patients (45 %). Twenty-four patients (55 %) were in the first CR or PR at the time of transplant. BEAM was used as a high-dose regimen in 36 patients (82 %) and all patients received peripheral blood grafts. The median follow-up for survivors was 46 (2-108) months from ASCT. Three patients died early from transplant-related reasons translating into a 2-year non-relapse mortality of 7 %. Relapse incidence at 4 years after ASCT was 39 %, with no events occurring beyond 2.5 years after ASCT. PFS and OS were 54 % and 59 % at four years, respectively. There was a trend for better OS in patients transplanted in the first CR or PR compared to more advanced disease status (70 % vs. 43 %, p=0.053). Of note, patients with a history of celiac disease had superior PFS (70 % vs. 35 %, p=0.02) and OS (70 % vs. 45 %, p=0.052) whilst age, gender, disease stage, B-symptoms at diagnosis or high-dose regimen were not associated with OS or PFS. Conclusions: This study shows for the first time in a larger patient sample that ASCT is feasible in selected patients with EATL and can yield durable disease control in a significant proportion of the patients. Patients transplanted in first CR or PR appear to do better than those transplanted later. ASCT should be considered in EATL patients responding to initial therapy.

Clinical characteristics, prognosis, and treatment of pelvic cryptorchid seminoma.

PURPOSE: To analyze the clinical characteristics, prognosis, and treatment outcome of pelvic cryptorchid seminoma (PCS), and to determine whether whole abdominal-pelvic irradiation for Stage I disease is necessary. METHODS AND MATERIALS: From 1958 to 1991, 60 patients with PCS were treated at the Cancer Hospital of Chinese Academy of Medical Sciences, Beijing. They presented with a lower abdominal mass and showed a predominance for the right side. A high proportion of patients with PCS [26 of 60 (43%)] had metastatic disease, compared to 20% of those with scrotal seminoma, and there was a tendency toward a higher frequency of pelvic nodal metastases. There were 34 Stage I, 6 Stage IIA, 11 Stage IIB, 5 Stage III, and 4 Stage IV patients. Of these 60 patients, 56 underwent laparotomy with or without cryptorchiectomy (37 radical orchiectomy, 7 partial orchiectomy, and 12 biopsy of the primary or cervical node), and 4 cervical node biopsy only. All patients were further treated with radiotherapy, chemotherapy, or a combination of both. Patients with Stage I and II disease received radiotherapy, whereas patients with Stage III and IV were treated with chemotherapy. RESULTS: The overall and disease-free survivals at 5 and 10 years were 92% and 87%, and 88% and 84%, respectively. The 5- and 10-year survivals were 100% for Stage I, 94% and 87% for Stage II, and 56% and 42% for Stage III/IV, respectively (p < 0.05). Volume of irradiation, i.e., whole abdominal-pelvic radiotherapy (10 patients), versus hockey-stick encompassing paraaortic, ipsilateral iliac nodes and the primary tumor or tumor bed (17) did not influence outcome in Stage I patients. Five patients relapsed within 2-12 years after treatment, and four of these patients were successfully salvaged. Four patients developed a second malignant tumor and died. CONCLUSION: Stage I and II PCS can be adequately controlled by radiotherapy regardless of the surgical procedure. Whole abdominal-pelvic irradiation for Stage I and IIA disease is not required, and fields can be limited to the paraaortic, ipsilateral iliac nodes and primary tumor or tumor bed. We recommend platinum-based chemotherapy for Stage IIB-IV PCS.

Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer.

BACKGROUND: To improve the efficacy of first-line therapy for advanced non-small cell lung cancer (NSCLC), additional maintenance chemotherapy may be given after initial induction chemotherapy in patients who did not progress during the initial treatment, rather than waiting for disease progression to administer second-line treatment. Maintenance therapy may consist of an agent that either was or was not present in the induction regimen. The antifolate pemetrexed is efficacious in combination with cisplatin for first-line treatment of advanced NSCLC and has shown efficacy as a maintenance agent in studies in which it was not included in the induction regimen. We designed a phase III study to determine if pemetrexed maintenance therapy improves progression-free survival (PFS) and overall survival (OS) after cisplatin/pemetrexed induction therapy in patients with advanced nonsquamous NSCLC. Furthermore, since evidence suggests expression levels of thymidylate synthase, the primary target of pemetrexed, may be associated with responsiveness to pemetrexed, translational research will address whether thymidylate synthase expression correlates with efficacy outcomes of pemetrexed. METHODS/DESIGN: Approximately 900 patients will receive four cycles of induction chemotherapy consisting of pemetrexed (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Patients with an Eastern Cooperative Oncology Group performance status of 0 or 1 who have not progressed during induction therapy will randomly receive (in a 2:1 ratio) one of two double-blind maintenance regimens: pemetrexed (500 mg/m2 on day 1 of a 21-day cycle) plus best supportive care (BSC) or placebo plus BSC. The primary objective is to compare PFS between treatment arms. Secondary objectives include a fully powered analysis of OS, objective tumor response rate, patient-reported outcomes, resource utilization, and toxicity. Tumor specimens for translational research will be obtained from consenting patients before induction treatment, with a second biopsy performed in eligible patients following the induction phase. DISCUSSION: Although using a drug as maintenance therapy that was not used in the induction regimen exposes patients to an agent with a different mechanism of action, evidence suggests that continued use of an agent present in the induction regimen as maintenance therapy enables the identification of patients most likely to benefit from maintenance treatment.

Appropriate end-points for right results in the age of antiangiogenic agents: Future options for phase II trials in patients with recurrent glioblastoma.

The progression-free survival rate at 6months (PFS-6) has long been considered the best end-point for assessing the efficacy of new agents in phase II trials in patients with recurrent glioblastoma. However, due to the introduction of antiangiogenic agents in this setting, and their intrinsic propensity to alter neuroradiological disease assessment by producing pseudoregression, any end-point based on neuroradiological modifications should be reconsidered. Further, statistically significant effects on progression-free survival (PFS) only should not automatically be considered reliable evidence of meaningful clinical benefit. In this context, because of its direct and unquestionable clinical relevance, overall survival (OS) represents the gold standard end-point for measuring clinical efficacy, despite the disadvantage that it is influenced by subsequent therapies and usually takes longer time to be evaluated. Therefore, while awaiting novel imaging criteria for response evaluation and/or new imaging tools to distinguish between 'true' and 'pseudo'-responses to antiangiogenic agents, the measurement of OS or OS rates should be considered primary end-points, also in phase II trials with these agents.

Long-term follow-up of follicular lymphoma (FL) patients receiving single agent rituximab at two different schedules in trial SAKK 35/98

Background: In FL, Rituximab as a single agent delivered in the standard schedule (4 times weekly) may induce a response rate of 50−70% with an event-free survival (EFS) of 1−3 years according to patients' characteristics. Prolonged Rituximab exposure seems to improve EFS at least in responding patients and to increase the rate of longterm responders. Here we report long-term results of a clinical trial comparing single agent Rituximab delivered in the standard schedule versus prolonged exposure, with focus on the proportion of long-term responders and their characteristics. Material and Methods: Between 1998 and 2002, chemotherapy na¨ıve (n = 64) or pre-treated (n = 138) FL patients received Rituximab in the standard schedule. Those responding or with stable disease were randomized to no further treatment (observation, n = 78) or 4 additional doses of Rituximab given at 2-month intervals (prolonged exposure, n = 73). EFS was calculated from the first dose of standard schedule until progression, relapse, second tumor or death. Results: At a median follow up of 9.4 years and with all living patients having been followed for at least 5 years, the median EFS is 13 months for the observation and 24 months for the prolonged exposure arm (p = 0.0007). In the observation arm 13% had no event at 5-years and only 4% at 8 years, while in the prolonged exposure arm it was 27% at 5 years and remained 21% at 8 years. The only significant prognostic factor for EFS in a multivariate Cox regression was the prolonged Rituximab schedule (hazard ratio 0.58, CI 0.39−0.86, p = 0.007), whereas being chemotherapy na¨ıve, presenting with stage

R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study.

BACKGROUND The role of re-treatment with rituximab in aggressive B-cell lymphomas still needs to be defined. This study evaluated the influence of prior exposure to rituximab on response rates and survival in patients with diffuse large B-cell lymphoma treated with rituximab plus etoposide, cytarabine, cisplatinum and methylprednisolone (R-ESHAP). DESIGN AND METHODS We retrospectively analyzed 163 patients with relapsed or refractory diffuse large B-cell lymphoma who received R-ESHAP as salvage therapy with a curative purpose. Patients were divided into two groups according to whether rituximab had been administered (n=94, "R+" group) or not (n=69, "R-" group) prior to R-ESHAP. RESULTS Response rates were significantly higher in the R- group in the univariate but not in the multivariate analysis. In the analysis restricted to the R+ group, we observed very low complete remission and overall response rates in patients with primary refractory disease (8% and 33%, respectively), as compared to those in patients who were in first partial remission (41% and 86%) or who had relapsed disease (50% and 75%) (p<0.01 in both cases). Overall, 60% and 65% of patients in the R+ and R- groups, respectively, underwent stem-cell transplantation after the salvage therapy. With a median follow-up of 29 months (range, 6-84), patients in the R+ group had significantly worse progression-free survival (17% vs. 57% at 3 years, p<0.0001) and overall survival (38% v 67% at 3 years, p=0.0005) than patients in the R- group. Prior exposure to rituximab was also an independent adverse prognostic factor for both progression-free survival (RR: 2.0; 95% CI: 1.2-3.3, p=0.008) and overall survival (RR: 2.2; 95% CI: 1.3-3.9, p=0.004). CONCLUSIONS R-ESHAP was associated with a high response rate in patients who were not refractory to upfront rituximab-based chemotherapy. However, the survival outcome was poor for patients previously exposed to rituximab, as compared to in those who had not previously been treated with rituximab.

Epigenetic regulation of human cancer/testis antigen gene, HAGE, in chronic myeloid leukemia.

BACKGROUND AND OBJECTIVES Cancer testis antigens (CTA) provide attractive targets for cancer-specific immunotherapy. Although CTA genes are expressed in some normal tissues, such as the testis, this immunologically protected site lacks MHC I expression and as such, does not present self antigens to T cells. To date, CTA genes have been shown to be expressed in a range of solid tumors via demethylation of their promoter CpG islands, but rarely in chronic myeloid leukemia (CML) or other hematologic malignancies. DESIGN AND METHODS In this study, the methylation status of the HAGE CTA gene promoter was analyzed by quantitative methylation-specific polymerase chain reaction (MSP) and sequencing in four Philadelphia-positive cell lines (TCC-S, K562, KU812 and KYO-1) and in CML samples taken from patients in chronic phase (CP n=215) or blast crisis (BC n=47). HAGE expression was assessed by quantitative reverse transcriptase-polymerase chain reaction. RESULTS The TCC-S cell line showed demethylation of HAGE that was associated with over-expression of this gene. HAGE hypomethylation was significantly more frequent in BC (46%) than in CP (22%) (p=0.01) and was correlated with high expression levels of HAGE transcripts (p<0.0001). Of note, in CP-CML, extensive HAGE hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (p=0.01) or imatinib (p=0.01), molecular response to imatinib (p=0.003) and progression-free survival (p=0.05). INTERPRETATIONS AND CONCLUSION: The methylation status of the HAGE promoter directly correlates with its expression in both CML cell lines and patients and is associated with advanced disease and poor outcome.

Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma. Results of the HDR-ALLO study - a prospective clinical trial by the Grupo Español de Linfomas/Trasplante de Médula Osea (GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation.

BACKGROUND Although Hodgkin's lymphoma is a highly curable disease with modern chemotherapy protocols, some patients are primary refractory or relapse after first-line chemotherapy or even after high-dose therapy and autologous stem cell transplantation. We investigated the potential role of allogeneic stem cell transplantation in this setting. DESIGN AND METHODS In this phase II study 92 patients with relapsed Hodgkin's lymphoma and an HLA-identical sibling, a matched unrelated donor or a one antigen mismatched, unrelated donor were treated with salvage chemotherapy followed by reduced intensity allogeneic transplantation. Fourteen patients showed refractory disease and died from progressive lymphoma with a median overall survival after trial entry of 10 months (range, 6-17). Seventy-eight patients proceeded to allograft (unrelated donors, n=23). Fifty were allografted in complete or partial remission and 28 in stable disease. Fludarabine (150 mg/m(2) iv) and melphalan (140 mg/m(2) iv) were used as the conditioning regimen. Anti-thymocyte globulin was additionally used as graft-versus-host-disease prophylaxis for recipients of grafts from unrelated donors. RESULTS The non-relapse mortality rate was 8% at 100 days and 15% at 1 year. Relapse was the major cause of failure. The progression-free survival rate was 47% at 1 year and 18% at 4 years from trial entry. For the allografted population, the progression-free survival rate was 48% at 1 year and 24% at 4 years. Chronic graft-versus-host disease was associated with a lower incidence of relapse. Patients allografted in complete remission had a significantly better outcome. The overall survival rate was 71% at 1 year and 43% at 4 years. CONCLUSIONS Allogeneic stem cell transplantation can result in long-term progression-free survival in heavily pre-treated patients with Hodgkin's lymphoma. The reduced intensity conditioning approach significantly reduced non-relapse mortality; the high relapse rate represents the major remaining challenge in this setting. The HDR-Allo trial was registered in the European Clinical Trials Database (EUDRACT, https://eudract.ema.europa.eu/) with number 02-0036.