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Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m2 daily for 5 days, etoposide 75 mg/m2 daily for 5 days, and idarubicin 9 mg/m2 daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation ( P < .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm ( P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity.

The morbidity and mortality associated with current therapies for acute promyelocytic leukemia (APL) remain a significant clinical concern, despite improvements in patient survival. Consequently, the development of adjuvant therapies that increase efficacy while reducing morbidities is important. Reducing the concentration of the toxic drugs in adjuvant therapy has the potential to reduce unwanted side effects. Therefore, this study aimed to determine the synergistic effects of fucoidan, an anti-tumor agent, with current APL therapies. When the human APL cell line, NB4, was treated in vitro with fucoidan plus ATO and ATRA at therapeutic and sub-therapeutic doses, there was an increase in sub-G0/G1 cells, annexin V/PI-positive-apoptotic cells and DNA fragmentation. This reduction in proliferation and increase in apoptosis was accompanied by enhanced myeloid differentiation as indicated by an increased expression of CD11b. This was not observed with the AML cell line Kasumi-1, suggesting specificity for APL. In vivo treatment of APL-bearing mice with fucoidan+ATRA or fucoidan+ATO delayed tumor growth, induced differentiation and increased tumor volume doubling time. The differentiated APL cells derived from the excised tumor mass exhibited decreased CD44 expression in fucoidan+ATRA treated mice. This could translate to decreased cell migration in APL patients. Our findings provide evidence supporting the use of fucoidan as an adjuvant therapeutic agent in the treatment of APL.

Background We sought to determine whether the substantial benefits of topical nitroglycerin with first-line, platinum-based, doublet chemotherapy in advanced nonsmall-cell lung cancer (NSCLC) seen in a phase II trial could be corroborated in a rigorous, multicenter, phase III trial. Patients and methods Patients starting one of five, prespecified, platinum-based doublets as first-line chemotherapy for advanced NSCLC were randomly allocated treatment with or without nitroglycerin 25 mg patches for 2 days before, the day of, and 2 days after, each chemotherapy infusion. Progression-free survival (PFS) was the primary end point. Results Accrual was stopped after the first interim analysis of 270 events. Chemotherapy was predominantly with carboplatin and gemcitabine (79%) or carboplatin and paclitaxel (18%). The final analysis included 345 events in 372 participants with a median follow-up of 33 months. Topical nitroglycerin had no demonstrable effect on PFS [median 5.0 versus 4.8 months, hazard ratio (HR) = 1.07, 95% confidence interval (CI) 0.86–1.32, P = 0.55], overall survival (median 11.0 versus 10.3 months, HR = 0.99, 95% CI 0.79–1.24, P = 0.94), or objective tumor response (31% versus 30%, relative risk = 1.03, 95% CI 0.82–1.29, P = 0.81). Headache, hypotension, syncope, diarrhea, dizziness, and anorexia were more frequent in those allocated nitroglycerin. Conclusion The addition of topical nitroglycerin to carboplatin-based, doublet chemotherapy in NSCLC had no demonstrable benefit and should not be used or pursued further. Clinical Trials Number Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.

To the editor: The application of rapid and affordable genome sequencing technologies to families with a high incidence of hematological malignancies (HMs) provides significant opportunities for understanding the genetic causes of these cancers.[1][1] In one of the few studies published to date

Telomere length has a biological link to cancer, with excessive telomere shortening leading to genetic instability and resultant malignant transformation. Telomere length is heritable and genetic variants determining telomere length have been identified. Telomere biology has been implicated in the development of hematological malignancies (HMs), therefore, closer examination of telomere length in HMs may provide further insight into genetic etiology of disease development and support for telomere length as a prognostic factor in HMs. We retrospectively examined mean relative telomere length in the Tasmanian Familial Hematological Malignancies Study using a quantitative PCR method on genomic DNA from peripheral blood samples. Fifty-five familial HM cases, 191 unaffected relatives of familial HM cases and 75 non-familial HM cases were compared with 758 population controls. Variance components modeling was employed to identify factors influencing variation in telomere length. Overall, HM cases had shorter mean relative telomere length (p=2.9×10-6) and this was observed across both familial and non-familial HM cases (p=2.2x10-4 and 2.2x10-5, respectively) as well as additional subgroupings of HM cases according to broad subtypes. Mean relative telomere length was also significantly heritable (62.6%; p=4.7x10-5) in the HM families in the present study. We present new evidence of significantly shorter mean relative telomere length in both familial and non-familial HM cases from the same population adding further support to the potential use of telomere length as a prognostic factor in HMs. Whether telomere shortening is the cause of or the result of HMs is yet to be determined, but as telomere length was found to be highly heritable in our HM families this suggests that genetics driving the variation in telomere length is related to HM disease risk.

Background: Although the use of complementary and alternative medicines is widespread in cancer patients, clinical evidence of their benefits is sparse. Furthermore, while they are often assumed to be safe with regard to concurrent use of anticancer therapies, few studies have been carried out to investigate possible interactions. Fucoidans are a group of sulfated carbohydrates, derived from marine brown algae, which have long been used as dietary supplements due to their reported medicinal properties, including anticancer activity. The aim of this study was to investigate the effect of co-administration of fucoidan, derived from Undaria pinnatifida, on the pharmacokinetics of 2 commonly used hormonal therapies, letrozole and tamoxifen, in patients with breast cancer. Methods: This was an open label non-crossover study in patients with active malignancy taking letrozole or tamoxifen (n = 10 for each group). Patients took oral fucoidan, given in the form of Maritech extract, for a 3-week period (500 mg twice daily). Trough plasma concentrations of letrozole, tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using HPLC-CAD (high-performance liquid chromatography charged aerosol detector), at baseline and after concomitant administration with fucoidan. Results: No significant changes in steady-state plasma concentrations of letrozole, tamoxifen, or tamoxifen metabolites were detected after co-administration with fucoidan. In addition, no adverse effects of fucoidan were reported, and toxicity monitoring showed no significant differences in all parameters measured over the study period. Conclusions: Administration of Undaria pinnatifida fucoidan had no significant effect on the steady-state trough concentrations of letrozole or tamoxifen and was well tolerated. These results suggest that fucoidan in the studied form and dosage could be taken concomitantly with letrozole and tamoxifen without the risk of clinically significant interactions.

Background Bevacizumab is an antiangiogenic mAb with efficacy against several cancers, but it is associated with risk of arterial thromboembolism (ATE). Further data are needed to determine the safety of bevacizumab. Patients and methods We recorded grade 3, 4, or 5 ATE events and other data (including age, baseline cardiovascular risk factors, history of ATE, and aspirin use) from 471 patients with metastatic colorectal cancer in the MAX (Mitomycin, Avastin, Xeloda) trial of capecitabine monotherapy versus capecitabine with bevacizumab with or without mitomycin C. Results Bevacizumab-treated patients had 12 grade 3, 4, or 5 ATEs (3.8% incidence). ATEs occurred in 2.1% of patients >65 years, 5% of those with a history of ATE, and 5% of those with cardiac risk factors. Age, history of ATE, or vascular risk factors did not increase risk. Aspirin users had a higher incidence than nonusers (8.9% versus 2.7%) but had higher rates of vascular risk factors. Conclusions Bevacizumab was associated with a modestly higher risk of ATE, but safety was not significantly worse in older patients or patients with a history of ATE or vascular risk factors. The effect of aspirin in preventing ATE in patients receiving bevacizumab could not be determined from this study.

Objective. Transplantation of hematopoietic progenitor stem cells (HPC) is an important treatment modality for a variety of neoplastic diseases. HPC collection for transplantation with granulocyte colony-stimulating factor may be unsuccessful in patients who have received prior chemotherapy or for other reasons. Methods to improve mobilization of HPCs are required. Disruption of the interaction between the cell surface receptor CXCR4 and its ligand stromal derived factor-1 (SDF-1) is a mechanism for HPC release from the bone marrow into the peripheral blood (PB). Methods. We carried out a clinical trial to evaluate the effects of ingestion of a fucoidan, galactofucan sulfate (a putative HPC mobilizing agent) on circulating CD34+ cells, CXCR4 expression, and levels of SDF-1, interferon gamma (IFN-g) and interleukin 12. Results. Following ingestion of fucoidan, CD34+ cells increased significantly in the PB from 1.64 to 1.84 cells/mL after 4 days. The proportion of CD34+ cells that expressed CXCR4 increased from 45 to 90% after 12 days, the plasma level of SDF-1 increased from 1978 to 2010 pg/mL, and IFN-g level increased from 9.04 to 9.89 pg/mL. Conclusion. Oral fucoidan significantly amplified the CXCR4+ HPC population. The ability to mobilize HPC using sulfated polysaccharides and mobilize more HPC with high levels of CXCR4 could be clinically valuable.

Background Harvesting of hemopoietic stem cells (HSC) from G-CSF-primed BM for autologous transplantation is an alternative to collection of unprimed BM or G-CSF-primed peripheral blood (PB). However, the optimum number of days of G-CSF administration for this purpose is unknown. We set out to determine whether cell yields could be optimized by varying the number of days of G-CSF administration prior to BM stem cell harvesting. Methods We conducted a randomized controlled single-center trial of 6 days (the standard) vs. 4 days of G-CSF administration and compared yields of total nucleated cells (TNC), CD34 + HSC and CFU-GM cells per kilogram patient body weight. Statistical analysis was by Student's t -test. Results Twenty-four patients were enrolled; 13 received 6 days and 11 received 4 days of G-CSF administration. Analysis of the first harvest aspirate showed higher proportions of CD34 + HSC ( P =0.02) and CFU-GM ( P =0.03) in the 4-day group. For the 6-day and 4-day groups, respectively, the median yield of TNC/kg was 6.5×10 8 and 5.4×10 8 ( P =0.28), of CD34 + cells/kg 0.56×10 6 and 0.98×10 6 ( P =0.04) and of CFU-GM cells/kg 1.66×10 5 and 1.55×10 5 ( P =0.75). Discussion These results suggest that by 6 days the HSC-stimulating effect of G-CSF has passed its peak and that 4 days should be adopted as the standard for G-CSF priming prior to BM stem cell harvesting for autologous transplantation.

There is a wide variety of cancer types yet, all share some common cellular and molecular behaviors. Most of the chemotherapeutic agents used in cancer treatment are designed to target common deregulated mechanisms within cancer cells. Many healthy tissues are also affected by the cytotoxic effects of these chemical agents. Fucoidan, a natural component of brown seaweed, has anti-cancer activity against various cancer types by targeting key apoptotic molecules. It also has beneficial effects as it can protect against toxicity associated with chemotherapeutic agents and radiation. Thus the synergistic effect of fucoidan with current anti-cancer agents is of considerable interest. This review discusses the mechanisms by which fucoidan retards tumor development, eradicates tumor cells and synergizes with anti-cancer chemotherapeutic agents. Challenges to the development of fucoidan as an anti-cancer agent will also be discussed.

Background We hypothesised that alternating inhibitors of the vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin pathways would delay the development of resistance in advanced renal cell carcinoma (aRCC). Patients and methods A single-arm, two-stage, multicentre, phase 2 trial to determine the activity, feasibility, and safety of 12-week cycles of sunitinib 50 mg daily 4 weeks on / 2 weeks off, alternating with everolimus 10 mg daily for 5 weeks on / 1 week off, until disease progression or prohibitive toxicity in favourable or intermediate-risk aRCC. The primary end point was proportion alive and progression-free at 6 months (PFS6m). The secondary end points were feasibility, tumour response, overall survival (OS), and adverse events (AEs). The correlative objective was to assess biomarkers and correlate with clinical outcome. Results We recruited 55 eligible participants from September 2010 to August 2012. Demographics: mean age 61, 71% male, favourable risk 16%, intermediate risk 84%. Cycle 2 commenced within 14 weeks for 80% of participants; 64% received ≥22 weeks of alternating therapy; 78% received ≥22 weeks of any treatment. PFS6m was 29/55 (53%; 95% confidence interval [CI] 40% to 66%). Tumour response rate was 7/55 (13%; 95% CI 4% to 22%, all partial responses). After median follow-up of 20 months, 47 of 55 (86%) had progressed with a median progression-free survival of 8 months (95% CI 5–10), and 30 of 55 (55%) had died with a median OS of 17 months (95% CI 12–undefined). AEs were consistent with those expected for each single agent. No convincing prognostic biomarkers were identified. Conclusions The EVERSUN regimen was feasible and safe, but its activity did not meet pre-specified values to warrant further research. This supports the current approach of continuing anti-VEGF therapy until progression or prohibitive toxicity before changing treatment. Australian New Zealand Clinical Trials Registry ACTRN12609000643279.

In this prospective multicentre trial, 90 patients undergoing autologous stem cell transplantation (ASCT) were randomised to receive (n=43) or not receive (n=47) amifostine 910 mg/m(2) prior to melphalan 200 mg/m(2). Patients were monitored for regimen-related toxicity, engraftment, supportive care, response and survival. Both groups underwent ASCT at a median of 8 months from diagnosis and were matched for disease characteristics, prior therapy and pre-ASCT disease responsiveness. Amifostine infusional side-effects were frequent, occurring in 65% of patients, but of mild severity. Amifostine use was associated with a reduction in the median grade of oral mucositis (1 vs 2, P=0.01) and the frequency of severe (WHO grades 3 or 4) mucositis (12 vs 33%, P=0.02), but no reduction in the requirement for parenteral nutrition or analgesic use. Conversion to complete remission post-ASCT occurred in 30 and 14% of the amifostine and control groups, respectively (P=0.09). With a median follow-up of 35 months, there was no statistically significant difference between the median progression-free or overall survival times for the two groups. We conclude that amifostine can be safely administered prior to high-dose melphalan and significantly reduces the frequency and severity of therapy-induced oral mucositis.

We describe a collection of 11 families with ≥ 2 generations of family members whose condition has been diagnosed as a hematologic malignancy. In 9 of these families there was a significant decrease in age at diagnosis in each subsequent generation (anticipation). The mean age at diagnosis in the first generation was 67.8 years, 57.1 years in the second, and 41.8 years in the third (P < .0002). This was confirmed in both direct parent-offspring pairs with a mean reduction of 19 years in the age at diagnosis (P = .0087) and when the analysis was repeated only including cases of mature B-cell neoplasm (P = .0007). We believe that these families provide further insight into the nature of the underlying genetic mechanism of predisposition in these families.

We studied interleukin-6 (IL-6) levels on the day of transplantation in 31 patients undergoing autologous haemopoietic stem cell transplantation (SCT) (either peripheral blood stem cell transplantation (PBSCT) or bone marrow transplantation (BMT)) for neoplastic diseases to determine if there was a relationship between IL-6 level and rate of haemopoietic recovery, length of stay in hospital, and survival. There was no apparent delay in post-transplant recovery associated with elevated IL-6 levels. However, increased values of IL-6 tended to be associated with an increased length of stay in hospital (P = 0.083). There was a highly significant adverse association between higher IL-6 levels and survival following transplantation (P = 0.0001). This association remained significant (P = 0.013) in the uniform subgroup of patients with malignant lymphoma with chemosensitive disease who had undergone BMT (that is, excluding patients who had undergone PBSCT) (n = 13). Knowledge of IL-6 levels on the day of transplant has the potential to provide valuable prognostic information in patients undergoing autologous haemopoietic SCT.

Patterns of failure were studied in two consecutive randomized trials of intensified induction therapy carried out by the Australian Leukaemia Study Group (ALSG) between 1984 and 1991 to determine the impact of dose intensification. Patients received standard dose cytarabine and daunorubicin (7-3), 7-3 plus etoposide (7-3-7) or 7-3 plus high-dose cytarabine (HIDAC-3-7) chemotherapy. Patients with FAB M3 morphology were excluded. Time to failure (TTF) was defined as the time from randomization to induction death or removal from study for non-responders, or to relapse or death in complete response (CR) for complete responders. An estimated 86% of 470 de novo patients with acute myeloid leukaemia failed within 10 years of randomization, as a result of death in induction in 17% of the randomized patients, failure to achieve CR in a further 17%, relapse in 44% and death in CR in 8% of patients. An estimated 66% of patients failed as a result of refractory disease or relapse within that period (disease-related failures). Multifactor analysis identified age and peripheral blast count as the most significant pretreatment factors associated with overall TTF. These factors, together with cytogenetics, were significantly associated with disease-related failures. High-dose cytarabine in induction significantly decreased the disease-related failure rate as did allogeneic transplantation in first CR. The impact of high-dose cytarabine did not depend on the cytogenetic risk group.

Background: Anthracylines are one of the major classes of drugs active against acute myeloid leukemia (AML). Increased doses of daunorubicin during induction therapy for AML have been shown to improve remission rates and survival. The ALLG used idarubicin in induction therapy at a dose of 9 mg/m2 x 3 days (total dose 27 mg/m2) in combination with high-dose cytarabine and etoposide (Blood 2005, 105:481), but showed that a total idarubicin dose of 36 mg/m2 was too toxic in this context (Leukemia 2001, 15:1331). In order to further improve outcomes in adult AML by anthracycline dose escalation, we conducted a phase 3 trial comparing standard to an increased idarubicin dose during consolidation therapy. Methods: Patients achieving complete remission after 1 or 2 cycles of intensive induction therapy (idarubicin 9 mg/m2 daily x3, cytarabine 3 g/m2 twice daily on days 1,3,5 and 7, and etoposide 75 mg/m2 daily x7; ICE protocol) were randomized to receive 2 cycles of consolidation therapy with cytarabine 100 mg/m2 per day for 5 days, etoposide 75 mg/m2 for 5 days, and idarubicin 9mg/m2 daily for either 2 or 3 days (standard and intensive arms respectively). No further protocol therapy was given. The primary endpoint was leukemia-free survival from randomization to consolidation therapy (LFS) with overall survival (OS) as secondary endpoint. Results: A total of 422 patients with AML (excluding cases with CBF rearrangements or APL) aged 16 to 60 years were enrolled between 2003-10, with 345 (82%) achieving complete remission, and 293 being randomized to standard (n=146) or intensive (n=147) consolidation arms. The median age was 45 years in both arms (range 16- 60), and both groups were balanced for intermediate versus unfavorable karyotypes and for frequency of mutations involving FLT3-ITD and NPM1 genes. Of the randomized patients, 120 in the standard arm (82%) and 95 in the intensive arm (65%) received the second consolidation cycle (p Conclusion: We conclude that in adult patients in complete remission after intensive induction chemotherapy an increased dose of idarubicin delivered during consolidation therapy results in improved LFS, without increased non-hematologic toxicity. Figure 1. Figure 1. Disclosures Szer: Ra Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees. Marlton:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wei:Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; CTI: Consultancy, Honoraria; Abbvie: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Cartwright:ROCHE: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roberts:Servier: Research Funding; Janssen: Research Funding; Genentech: Research Funding; AbbVie: Research Funding. Mills:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance sponsorship. Gill:Janssen: Membership on an entity's Board of Directors or advisory committees. Seymour:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Purpose The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. Patients and Methods In total, 477 patients with CD20+ DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. Results After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). Conclusion In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.

A family history of a haematological malignancy (HM) is known to be a risk factor for HMs. However, collections of large families with multiple cases of varied disease types are relatively rare. We describe a collection of 12 families with dense aggregations of multiple HM subtypes. Cases were ascertained from a population based study conducted between 1972 and 1980 in Tasmania, Australia. Diagnoses were confirmed through review and re-examination of stored tissue, pathology reports, Tasmanian Cancer Registry and flow cytometry records. Family trees were generated and kinship coefficients were calculated for all pairs of affected individuals. 120 cases were found in these families. Cases diagnosed with chronic lymphocytic leukaemia (CLL) demonstrated the most significantly increased aggregation (P 53 years), did not aggregate together in families with disease that presented at an earlier age (

As part of an epidemiological survey of myelodysplastic syndromes (MDS) in southern Tasmania, 62 MDS patients identified over a 2 year period were tested for the presence of CD34, the human progenitor cell antigen (HPCA), in their peripheral blood. The results were correlated with transformation to acute myeloid leukemia (AML) and patient survival, and CD34+ status was compared as a prognostic indicator with Bournemouth score, cytogenetics, and CFU-GM colony growth which were also assessed. Circulating CD34+ cells were found in 23 of the 62 MDS patients; 9 of the 23 patients with circulating CD34+ cells transformed to AML, as compared with none of the 39 CD34 negative patients (P less than 0.0001); and 11 of the 23 patients with circulating CD34+ cells were dead at the end of the 2 year period, as opposed to 6 of the 39 with no CD34+ cells (P less than 0.03). The Bournemouth score was also significantly associated with transformation to AML (P less than 0.0001) and poor survival (P less than 0.04). These were the only significant associations of the possible prognostic factors studied with either transformation or survival. In summary, the presence of circulating CD34+ cells was significantly associated with both progression to AML and poor survival and was found to be a better prognostic indicator than cytogenetics or CFU-GM colony growth.

Previously untreated patients with acute nonlymphocytic leukemia (ANLL) aged 15 to 70 years were randomized to either cytosine arabinoside 100 mg/m2/d continuous intravenous (IV) infusion days 1 through 7, daunorubicin 50 mg/m2/d IV days 1 through 3 (7–3), or the same drugs intensified with etoposide 75 mg/m2/d IV days 1 through 7 (7–3–7) as induction therapy. Patients achieving complete remission (CR) received two courses of consolidation therapy (5–2 or 5–2–5) followed by maintenance therapy. Of 264 eligible patients, CR occurred in 56% of 7– 3 and 59% of 7–3–7 patients; 7–3–7 significantly improved remission duration (P = .01). The median remission duration was 12 months for 7–3 and 18 months for 7–3–7. Survival was similar when the two arms were compared overall. Subset analysis performed to identify patients with the most benefit showed that etoposide significantly prolonged remission duration in younger patients (less than 55 years) with a median of 12 months for 7–3 and 27 months for 7–3–7 (P = .01). Survival appeared to be prolonged with 7–3–7 in patients aged less than 55 years, with a median of 9 months for 7–3 as compared with 17 months for 7–3–7 (P = .03). In older patients (aged greater than or equal to 55 years), 7–3–7 was more toxic, with significantly more severe [World Health Organization (WHO) grade 3 or 4] stomatitis (P = .02) and no additional clinical benefit. Hematologic toxicity for induction courses was similar, with granulocytopenia less than 0.5 x 10(9)/L for a median of 16 days per course for 7–3 and 15 days for 7–3–7. Hematologic toxicity was more severe for 5–2–5 consolidation courses (P = .003). Induction and consolidation therapy intensified with etoposide resulted in significantly improved remission duration but not survival.

The value of administering sequential courses of chemotherapy containing high-dose cytarabine in both induction and consolidation therapy for acute myeloid leukemia (AML) has not been assessed in a prospective randomized trial. Two hundred ninety-two AML patients aged 15 to 60 years were enrolled in the Australasian Leukaemia and Lymphoma Group (ALLG) AML trial number 7 (M7) protocol to evaluate this question. All received induction therapy with the ICE protocol (idarubicin 9 mg/m2 × 3; cytarabine 3 g/m2 twice a day on days 1, 3, 5, 7; etoposide 75 mg/m2 × 7). Complete remission was achieved in 234 (80%) patients. Two hundred two patients in remission were then randomized to either a further identical cycle of ICE or 2 attenuated courses (cytarabine 100 mg/m2 daily × 5, idarubicin × 2, etoposide × 5 [IcE]). ICE consolidation therapy was more toxic than IcE, however, the treatment-related death rate was not significantly different. There was no difference between the 2 consolidation arms for relapse-free survival at 3 years (49% for ICE vs 46% for IcE; P = .66), survival following randomization (61% vs 62%; P = .91), or the cumulative incidence of relapse (43% vs 51%; P = .31), and there was no difference within cytogenetic risk groups. Intensive induction chemotherapy incorporating high-dose cytarabine results in high complete remission rates, but further intensive consolidation treatment does not appear to confer additional benefit.

This is a book that had to be written. It tells the story of the development of tamoxifen from a failed ‘morning after’ pill to an enormously successful drug for the treatment of breast cancer in all its stages. This development proceeded because of the scientific astuteness and dedication of a handful of scientists and physicians who had to battle against the business plans of the original owners of the intellectual property. The story is a mixture of the personal journey of Craig Jordan—the man who is known as the ‘father of tamoxifen’ and pure science. Although Jordan is listed as the third co-author, this is really his story, which seems to have been partially ghost-written by the other two. This technique leads to some style confusion as the text is composed in a mixture of the first and third persons with the narrative switching from time to time between the two, often unaccountably. That minor criticism aside, for anyone who has been involved in the treatment of breast cancer over the years, this is a fascinating story. Jordan describes how he fell serendipitously into research on the drug, and how there has been increasing recognition of the value of tamoxifen as a treatment for breast cancer in all its stages (prevention, adjuvant, advanced). The descriptions of research on tamoxifen are equally detailed and up-to-date with respect to both the laboratory and the clinic. Jordan’s work could be described as the epitome of so-called translational research, illustrating just how to move a treatment from ‘bench to bedside’. Intriguingly, similar to the story of some more recent breakthrough cancer drugs (such as imatinib and filgrastim), the pharmaceutical company involved in tamoxifen’s early development had to be cajoled into bringing the drug to market, against their expectations that there was little likelihood of it benefitting their bottom line. Millions of patients later, and no doubt mega-millions of dollars later, tamoxifen has become probably the biggest selling anti-cancer drug of all time. This success is well deserved, as is explained well in the book. Forty years on, the drug is still widely used for treatment of breast cancer and has well and truly stood the test of time. In retrospect, tamoxifen could be considered the first successful ‘targeted treatment’ for cancer, although at the time of its initial testing, in the 1970s, the idea of treating cancer by use of a drug acting on a narrow ‘target’ did not even exist. This statement may surprise the current generation of cancer scientists, for whom the identification of a target and the subsequent logical development of a chemical agent to interfere with that target’s function are the sine qua nons of their existence. This book should be available in every oncology department. The story will interest clinicians and laboratory scientists alike. It has both historical value and value as a guide that will illuminate the path to successful involvement in cancer research for younger cancer researchers.

The Australian Leukaemia Study Group (ALSG) investigated whether G-CSF would accelerate haemopoietic recovery after induction treatment for acute myeloid leukaemia (AML) intensified with high-dose cytarabine, and therefore improve response rates and survival. Patients were randomised to receive lenograstim (glycosylated recombinant human G-CSF) 5 microg per kg body weight subcutaneously daily from day 8 after starting chemotherapy, or no cytokine, following chemotherapy with cytarabine 3 g/m2 every 12 h on days 1, 3, 5, and 7, together with idarubicin 9 or 12 mg/m2 on days 1, 2, and 3, plus etoposide 75 mg/m2 on days 1 to 7 inclusive. Patients had untreated AML, and were aged 16 to 60 years. Overall, 54 evaluable patients were randomised to receive lenograstim and 58 to no cytokine. Patients in the lenograstim arm had a significantly shorter duration of neutropenia0.5 x 10(9)/l compared to patients in the no cytokine arm (median 18 vs 22 days; P = 0.0005), and also shorter duration of total leucopenia1.0 x 10(9)/l (17 vs 19 days; P = 0.0002), as well as a reduction in duration of treatment with therapeutic intravenous antibiotics (20 vs 24 days; P= 0.015) and a trend to reduced number of days with fever38.0 degrees C (9 vs 12 days; P = 0.18). There were no differences between the two groups in platelet recovery, red cell or platelet transfusions, or non-haematological toxicities. For patients achieving CR after their first induction course, a reduction in the time to the start of the next course of therapy was observed in the lenograstim arm, from a median of 40.5 days to a median of 36 days (P = 0.082). The overall complete response rates to chemotherapy were similar, 81% in the lenograstim arm vs 75% for the no cytokine arm (P = 0.5), and there was no significant difference in the survival durations. We conclude that the granulopoietic stimulating effect of G-CSF is observed after induction therapy for AML intensified by high-dose cytarabine, resulting in an improvement in a number of clinically important parameters with no major adverse effects.

Abstract 4810 Diffuse large B-cell lymphoma (DLBCL) is a common subtype of aggressive non-Hodgkin lymphoma derived from germinal center (GC) and (post-) non-GC B-cells based on gene expression studies. Differences in five-year survival rates between these subtypes may be clinically relevant with enhanced survival for GC versus non-GC DLBCL. Although the adoption of R-CHOP as the new standard of care has led to improved outcomes, new treatment modalities are still needed. Seaweed derived galactofucan sulfate is already being widely used as a complimentary medicine by cancer patients. The medical community commonly criticizes the efficacy of naturopathic medicines, as they have not undergone evaluation in an accepted scientific manner. In an on going clinical trial we attempt to evaluate seaweed extracts with respect to its tolerability, safety and activity in cancer patients. In phase-I patients showed no toxicity for seaweed extract (TSE01) and the maximum dose was limited by patients' tolerability to take a number of capsules daily. In phase-II all patients received the 10gm/day of TSE01 or the maximum tolerated dosage observed from Phase-I. We found that a seaweed extract (TSE01) had anti-tumorigenic effects. At the same time different leukemia and lymphoma cell lines were treated with varying concentrations of seaweed extracts that were prepared in house. Cellular viability using the trypan blue exclusion assay, and apoptosis and necrosis using flow cytometric analysis (annexin V apoptosis assay) were studied in four different cell lines; OCI-LY-19, KG1, RL, and WSU-DLCL2. MTT assay was also used to measure the activity of living cells via mitochondrial dehydrogenase activity. RNA was isolated from all cell lines for further analysis. Any concentration of seaweed extract (CSE01) above 5.2 mM was found toxic to all cell lines. CSE01 used at 2.6 mM had an inhibitory effect on the growth of a non-GC DLBCL cell-line, OCI-LY-19, while having no effect on other non-lymphoma or leukemia cell lines. At this specific concentration, we monitored the expression of a panel of pathway or disease-specific genes using the RT2 profiler PCR array system. The human apoptosis pathway-finder PCR array profiles the expression of 84 key genes involved in apoptosis, or programmed cell death. The array includes the TNF ligands and their receptors; members of the bcl-2, caspase, IAP, TRAF, CARD, death domain, death effector domain, and CIDE families; as well as genes involved in the p53 and ATM pathways. After treatment with CSE01, only one cell line (OCI-LY-19) showed changes in the expression of 3 genes (FASLG, BIRC3, TNFRSF1A). A fold-up regulation of 4.4 in the BIRC3 was observed and fold-down regulation of -2.8 and -2088 in TNFRSF1A and FASLG was observed, subsequently. Down regulation of FASLG gene, a TNF ligand family member plays an important role in the apoptosis-induction through mitochondrial pathway of OCI-LY-19 cell line. Given the less favorable response to standard therapies for non-GC DLBCL, investigational approaches using new agents such as CSE01 may eventually improve treatment of these types of lymphoma. Disclosures: No relevant conflicts of interest to declare.

Sulfated glycans such as fucoidan have been shown to induce rapid hematopoietic progenitor stem cell (HPCs) mobilization in mice and primates. Our previous clinical study has demonstrated up-regulation of CXCR4 on peripheral CD34+ cells in volunteers who had received oral doses of 75% pure fucoidan. The aim of this study was to investigate the in vitro effects of fucoidan on a cytokine mediated CD34+ cell expansion system and to characterize the fucoidan effects on CD34+ proliferation and differentiation using a factorial design experiment and flow cytometry. Isolex selected CD34+ cells harvested from multiple myeloma patients were used in the study. There is institutional approval for the in vitro growth of CD34+ cells from mobilized peripheral blood. Fractional (25−1 resolution V, 16 runs, 2 blocks, E=ABCD) and full (24, 16 runs, 2 blocks) factorial design experiments were used to investigate the effects of depyrogenated fucoidan (DP-GFS) and cytokines on the growth of CD34+ cells. The cells were grown in 24 well dishes (1 ml/well) at an inoculum density of 20,000 cells/ml in serum free media and cultured for 10 days in a cytokine cocktail including G-CSF, FL, SCF, TPO and SDF1 each at two levels 100 ng/ml or 1000 ng/ml. DP-GFS was used in the cultures at four different levels including 0, 10, 100 and 500 μg/ml. Cells were then harvested and analyzed using three color flow cytometry and a panel of antibodies that includes CD15, CD14, CD41a, CD38, CD34, and CXCR4. The in vitro effect of DP-GFS on CXCR4 expression was opposite to that found in vivo using 75% fucoidan. At 100 ng/ml and at saturating levels of FL, SCF, TPO and G-CSF (1000 ng/ml), DP-GFS at 10 μg/ml was observed to reduce the number of CD34+ cells produced per input CD34+ cell (1.09±0.07 versus 0.84±0.05, n=16, p=0.002) and have a negative effect on the percentage of CD34+ cells that express CXCR4 (87.2±1.8 versus 77.4±2.3, n=16, p=0.001). There was no significant effect of DP-GFS on the total cellular output nor other cell subsets examined (CD41a+CD14−, CD15+, CD14+). Our in vitro results are more consistent with a recent clinical study that demonstrates down-regulation of CXCR4 receptors on CD34+ cells in G-CSF or GM-CSF mobilized blood (Dlubek et al, 2006). We hypothesize that fucoidan acts in vitro and in vivo via different mechanisms.

We have previously demonstrated significant anti-lymphoma activity using an outpatient-based salvage approach comprising vinorelbine and gemcitabine with an overall response (CR + PR) rate of 55%. We now report the results of a planned interim analysis of a similar outpatient approach for both non-Hodgkin’s lymphoma (NHL) and Hodgkin’s lymphoma (HL) but incorporating patient stratification and treatment escalation. Patients were stratified into Group 1 (G1 - good risk - first relapse following durable first remission - follicular NHL>12 months, all other NHL sub-types and HL>6 months); Group 2 (G2 - poor risk - primary refractory, second or subsequent relapse, or non-durable first remission); or Group 3 (G3 - post-transplant - relapse following any form of stem cell transplant therapy). Two chemotherapy regimens were evaluated. VGF (vinorelbine 25mg/sqm days 1 and 8, gemcitabine 1000mg/sqm days 1 and 8, pegfilgrastim 6mg SC day 9); F-GIV (same as VGF but with ifosfamide 3000mg/sqm day 1 with mesna uroepithelial protection). G1 and G3 commenced therapy with VGF and G2 with F-GIV. Following 2 cycles of therapy all patients were restaged. Any patients demonstrating disease progression were removed from trial. Responsive patients (>50% reduction in all previous sites of disease and gallium and/or FDG-PET negativity where baseline positivity was demonstrated) received 2 further cycles of the same therapy, the remainder ‘escalated’ therapy with F-GIV (G1 and G3) or IVAC (G2) (inpatient treatment with ifosfamide, VP-16 and Ara-C). A planned total of 90 patients were accrued between December 2002 and December 2004. Here we report on the first 88 patients (G1 = 26, G2 = 50, G3 = 12) with a median age of 57 years (range, 17–78). Diagnoses at entry were HL, n = 16 (nodular sclerosing = 13, mixed cellularity = 3) and NHL, n = 72 (diffuse large cell = 41, follicular = 16, others = 15). So far G1 and G2 have received 79 and 138 cycles of VGF and F-GIV, respectively, with grades 3/4 neutropenia or thrombocytopenia occurring in 24% and 18% (VGF) and 62% and 49% (F-GIV) of patients, respectively. Significant non-haematological toxicities were uncommon. Febrile neutropenia, hospital admission, treatment delay or dose-reductions occurred with 4%, 19%, 4%, 1% and 17%, 34%, 9%, 9% of VGF and F-GIV cycles, respectively. The 12 post-transplant patients (G3) have received 28 and 8 cycles of VGF and F-GIV, respectively, with no unexpected toxicities. Based on published standardised response criteria overall response (CR + Cru + PR) on an intention-to-treat basis after 2 to 4 cycles of treatment is 54% (CR 29%) (77% and 42% for G1 and G2, respectively). Diffuse large cell NHL patients have demonstrated response rates of 67% and 17% for G1 and G2 patients, respectively. Based on this planned interim analysis we conclude that both VGF and F-GIV can be safely administered on an outpatient basis and show activity against advanced lymphoma.

Mobilization of peripheral blood progenitor cells for hematopoietic rescue following autologous transplantation is usually achieved with the chemokine G-CSF. Engraftment potential is increased when higher levels of the receptor CXCR4 are noted on the hematopoietic progenitor stem cells (HPCs). It was previously reported that intravenous treatment with fucoidan or dextran sulfate, which are sulfated high molecular weight compounds, increased numbers of circulating mature white blood cells and HPCs in mice and nonhuman primates. This treatment also led to an increase in the pro-inflammatory cytokines IFN-γ and IL-12 levels in mice. In vitro treatment of bone marrow mononuclear cells with IFN-γ can up-regulate the expression of CXCR4 on granulocyte precursors and monocytes. We obtained ethics approval and informed consent to study the mobilization effect of orally ingested GFSTM (Galactofucan Sulfate), a seaweed-derived fucoidan, in healthy human volunteers in a single blinded placebo controlled phase I/II clinical study. Flow cytometry was used to monitor CXCR4 receptor on CD34+ stem cells. When moderate quantities (3 g/day) of seaweed containing 10% GFSTM were ingested, a slight increase in the total number of HPCs (CD34+) in the peripheral blood (PB) was observed, from 1.38 to 1.69 cells/μL (p=0.22, n=6). In addition, there was a small increase in the percentage of HPCs that expressed CXCR4 surface receptor, from 0.59 to 1.47 cells/μL, which is equivalent to 43% to 63% (p=0.19, n=6). Moreover, when 3 g/day of 75% GFSTM was ingested, a greater increase in the total number of HPCs (CD34+) in PB was observed, from 1.65 to 1.84 cells/μL (p=0.04, n=23). Furthermore, the percentage of HPCs that expressed CXCR4 increased from 0.746–1.652 cells/μL, which is equivalent to 45% to 90% (p=0.0002, n=23). Cytokine analysis, which was performed using ELISA to test for SDF-1 and IFN-γ, showed a significant increase in the plasma level of these cytokines. SDF-1 level was elevated from 1979 to 2068 pg/mL (p=0.051, n=10) and the level of IFN-γ from 9.04 to 9.90 pg/mL (p=0.007, n=10). These results suggest that GFSTM may modulate CXCR4 or disturb the SDF-1 gradient between bone marrow and PB. IFN-γ might play a role in the up-regulation of the expression of CXCR4 on CD34+ cells. To the authors’ knowledge, this is the first report of mobilization of HPCs by disruption of CXCR4/SDF-1 interaction using oral fucoidan.

High-dose chemotherapy with autologous hemopoietic stem cell (HSC) transplantation is an important treatment option for patients with refractory or relapsed non-Hodgkin or Hodgkin lymphoma (NHL or HL). Although it is customary to collect the HSCs at the time the need is apparent, in theory collections carried out at an earlier stage of the disease - preferably when the patient is in remission - may have advantages in that 1) such HSCs will have been less exposed to damaging cytotoxic chemotherapy and 2) early collections may be less likely to be contaminated with malignant cells. However such "prophylactic" or "rainy day" harvests may need to be stored for extended periods before use, raising questions about their functional capacity. Although laboratory studies of the effects of long-term storage on the viability and proliferative capacity of cryopreserved HSCs have demonstrated that the cells remain functional, there have been few studies of clinical outcomes after their reinfusion. Because we have had a long-standing policy of carrying out "rainy day" harvests, we have had the opportunity to retrospectively compare rates of neutrophil and platelet engraftment, and 30-day transplant related mortality (TRM), of patients undergoing HSC transplantation after short-term (0.5 x 109/L) was achieved by 12.2 ± 4.2 (SD) days and 14.2 ± 6.5 days post-reinfusion for the short- and longer-term groups respectively (P=0.14). Platelet support was required for a mean 6.6 ± 9.5 and 7.5 ± 7.1 days, respectively (P=0.7). These clinical results demonstrate that HSCs after long-term cryostorage retain engraftment potential similar to that of HSCs stored for lesser periods and that such cells are safe and efficacious for autologous transplantation.

A rapidly fatal T-cell lymphoma developed in a 25-year-old man who, over a period of seven years, had been treated with radiotherapy and combination chemotherapy for Hodgkin's disease (HD). Non-Hodgkin's lymphoma (NHL) is increasingly being recognized as a late sequel of therapy for HD, but this is the first case in which NHL of T-cell type has been identified in such circumstances.

Congenital dyserythropoietic anemia type II (CDA II) or HEMPAS is a genetic disease caused by plasma membrane abnormality. The enzymic defect of HEMPAS has been suggested to be the lowered activity of N- acetylglucosaminyltransferase II, resulting in lack of polylactosamine formation on proteins and leading to accumulation of polylactosaminyl lipids. In contrast to typical HEMPAS cases, cell-surface labeling of the erythrocytes of a HEMPAS variant G.K. showed an absence of polylactosamines either on proteins or on lipids. Fast-atom bombardment mass spectrometry analysis of G.K.'s erythrocyte glycopeptides detected a series of high mannose-type oligosaccharides, which were not detected in erythrocyte N-glycans of normal cells or of other HEMPAS cases: The former contains polylactosaminoglycans and the latter contains hybrid- type oligosaccharides. Keratansulfate (sulfated polylactosamines) in this patient's serum was abnormally low. The galactosyltransferase activity in microsomal membranes prepared from G.K.'s mononucleated cells was 24% of the normal level, whereas this enzyme activity in G.K.'s serum was comparatively higher than normal. Western blotting of G.K.'s membranes using antigalactosyltransferase antibodies showed that G.K. has reduced amounts of this enzyme present. The results collectively suggest that variant G.K. is defective in polylactosamine synthesis owing to the decreased quantity of the membrane-bound form of galactosyltransferase.