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Abstract 3281 Background: MEK (mitogen-activated extracellular signal-related kinase) is downstream of the RAS/RAF pathway and is activated by many upstream oncogenic drivers. GSK1120212 is a potent and selective allosteric inhibitor of MEK 1 and 2 kinases. In vitro, GSK1120212 inhibited proliferation of myeloid cell lines selectively as compared to lymphoid cell lines. This 2 part study of a single daily oral dosing regimen was conducted to define the recommended Phase 2 dose, evaluate pharmacokinetics, and assess preliminary activity in patients with relapsed or refractory AML, MDS, ALL or CMML. Methods: Subjects with WBC< 30,000/uL who met hepatic, renal and cardiac function criteria were eligible for participation. GSK1120212 was given orally, once daily in the following dose cohorts: 3mg loading dose followed by 1mg/day (n=3), 1mg/day without loading dose (n=1), and 2mg/day without loading dose (n=9). The loading dose was discontinued after cohort 1, based on findings in the phase I solid tumor study (J Clin Oncol 28:15s, 2010 (suppl, abstr 2503). Results: Fourteen subjects (10 with AML, 2 MDS transformed to AML, 1 MDS, 1 ALL) entered the trial. Eight were male, and median age was 65 years (range 33 to 85). Pharmacokinetic analysis showed that, upon repeat dosing, GSK1120212 exposure increased in a dose-proportional manner, had a small peak:trough ratio of approximately 4 and an effective half-life of approximately 7.7 days. Steady state concentrations were reached by day 15. Both single and repeat dose pharmacokinetics of GSK1120212 appeared to be similar to a phase I study in patients with solid tumors. Systemic exposure exceeded concentrations that inhibited in vitro leukemic cell proliferation. At the 2mg/day dose level (n=9), drug-related adverse events were diarrhea (7 overall; 6-Grade 1/2, 1-Grade 3), rash (3-Grade 1/2), fatigue (4-Grade 1/2), visual changes (3 Grade 1/2). One subject experienced a Grade 2 reversible serous retinopathy associated visual changes which resolved after drug discontinuation. One dose limiting toxicity was seen in a subject with disease-related Grade 4 thrombocytopenia and pneumonia who experienced a Grade 5 cerebrovascular accident possibly related to drug. One subject in the 2mg/day cohort achieved a CR; peripheral blast count was reduced from 30% at baseline to 0% and bone marrow blast count was reduced from 50% at baseline to 3%. During this time, platelet count increased from 48K to a maximum of 276K. Initial salutary effect was seen after 2 weeks on therapy and duration of CR was 4 weeks bone marrow blast count was 3% and 5%, respectively, at the beginning and end of the 4 week CR duration. Conclusion: GSK1120212 administered at 2mg/day orally was tolerable in subjects with relapsed or refractory AML and other leukemias. This dose regimen achieved plasma concentrations sufficient for target inhibition and showed preliminary anti-leukemic clinical activity. Based on these results, a phase II study in AML, MDS and CMML has been initiated. Disclosures: Borthakur: GlaxoSmithKline: Research Funding. Foran:GlaxoSmithKline: Research Funding. Kadia:GlaxoSmithKline: Research Funding. Jabbour:GlaxoSmithKline: Research Funding. Wissel:GlaxoSmithKline: Employment. Cox:GlaxoSmithKline: Employment. Xu:GlaxoSmithKline: Employment. Bauman:GlaxoSmithKline: Employment. Baccus:GlaxoSmithKline: Research Funding. Connor:GlaxoSmithKline: Research Funding. Cortes:GlaxoSmithKline: Research Funding. Kantarjian:GlaxoSmithKline: Research Funding.

Abstract 636 Activating mutations in the FLT3 RTK are present in ∼30% of AML patients (pts), who have a significantly worse prognosis than pts with wild type (WT) FLT3. AC220 is a novel 2nd generation RTK inhibitor with potent in vitro and in vivo activity in FLT3- and KIT-dependent tumor cell lines. It is highly selective for both WT and mutant FLT3 with significant activity against KIT. A first-in-human Phase 1 study investigating AC220 in predominantly relapsed or refractory AML pts, unselected for FLT3 mutations, was recently completed, using a standard 3+3 dose escalation with 50% dose increments. AC220 was administered once daily as an oral solution initially with an intermittent dosing (ID) regimen: 14 days on and 14 days off (1 cycle). Starting dose was escalated from 12 to 450 mg/day ID. Additional cohorts were investigated on a continuous dosing (CD) regimen: 200 and 300 mg/day for 28 days (1 cycle). A total of 76 pts (46 male, 30 female) were dosed with AC220. Median age was 60 yrs (23-86), median number of prior therapies was 4 (0-9), 12 pts had prior allogeneic transplant and 3 elderly pts (≥72 yrs) unfit for induction chemotherapy were previously untreated. Eighteen pts (24%) had FLT3 ITD mutations, 47 (62%) were WT, and 11 (14%) were undetermined. Pts were also evaluated for PK, phosphorylated (p) FLT3, pKIT, pSTAT5, and ex vivo plasma inhibitory activity. AC220 plasma exposure was sustained between dose intervals and continued to increase in a dose-proportional manner from 12 to 450 mg with a half-life of ∼1.5 days. An active metabolite, AC886, was detected that has similar potency and activity to AC220. Patient plasma at '12 mg potently inhibited pFLT3 in ex vivo FLT3-ITD cell lines and complete inhibition of pFLT3 in WT cell lines was observed at higher doses. Target inhibition was also observed, with suppression of pFLT3, pSTAT5 and pKIT in peripheral blasts. The most commonly reported possibly drug-related AEs were GI events, peripheral edema, and dysguesia, which were Grade ≤2. DLT was observed at 300 mg CD and 200 mg CD was declared as the MTD. Two pts at 300 mg CD had possibly study drug-related DLTs with grade 3 QTc prolongation, but had confounding factors including concomitant medications known to prolong QTc. Responses (IWG criteria) were observed in 23 (30%) pts. PR and CR were observed as low as the 18 and 40 mg cohorts, respectively. Most responses occurred within cycle 1. Overall, 9 (12%) pts had a complete response (CR) with 2 CR, 5 CRi, and 2 CRp. One of these pts also had complete resolution of leukemia cutis. In addition, 14 (18%) pts achieved PR. Overall median duration of response (MDOR) was 14 (4-62+) weeks and overall median survival (MS) was 14 (1-68+) weeks. In FLT3-ITD pts the MDOR was 12 (4-27+) weeks and the MS was 18 (3-42) weeks. In FLT3-WT pts the MDOR was 32 (8-62+) weeks and the MS was 11 (1-68+) weeks. 10 (56%) of 18 FLT3-ITD pts were responders (1 CR, 3 CRi, 6 PR), 9 (19%) of 47 FLT3-WT pts (1 CRi, 2 CRp, 6 PR), and 4 (36%) of 11 undetermined pts (1 CR, 1 CRi, 2 PR). At 200 mg CD (MTD expansion), 4 of 6 FLT3-ITD pts responded (1 CR, 1 CRp, 1 CRi, 1 PR). Of the 4 responders, 2 failed prior treatment with sorafenib and 2 previously refractory pts went onto transplant. The 2 FLT3-ITD non-responders had 6 and 8 prior lines of therapy, respectively. These encouraging efficacy results and an acceptable safety profile warrant continued evaluation of AC220 as monotherapy and in combination therapy for the treatment of AML. Phase 2 studies in FLT3-ITD positive and WT pts are in progress. Disclosures: Cortes: Ambit Biosciences: Research Funding. Foran:Ambit Biosciences: Research Funding. Ghirdaladze:Ambit Biosciences: Research Funding. DeVetten:Ambit Biosciences: Research Funding. Zodelava:Ambit Biosciences: Research Funding. Holman:Ambit Biosciences: Research Funding. Levis:Ambit Biosciences: Consultancy, Research Funding. James:Ambit Biosciences: Employment. Zarringkar:Ambit Biosciences: Employment. Gunawardane:Ambit Biosciences: Employment. Armstrong:Ambit Biosciences: Employment. Padre:Ambit Biosciences: Employment. Wierenga:Ambit Biosciences: Employment. Corringham:Ambit Biosciences: Employment. Trikha:Ambit Biosciences: Employment.

Abstract 2076 Poster Board II-53 Background Recently, further refinement of the “unfavorable” cytogenetic category in AML demonstrated that a “monosomal karyotype” (MK+) – defined as two or more distinct autosomal chromosome monosomies or one single autosomal monosomy in the presence of structural abnormalities – carries a markedly inferior prognosis to that of a “non-monosomal karyotype” (MK-) – defined as a group with various non-core binding factor (CBF) cytogenetic abnormalities but who are MK negative (J. Clin Onc 26:4791). This finding was based on data from patients predominantly with de novo AML. We analysed data from a phase II trial of patients with sAML to examine whether the monosomal karyotype is also predictive of poor outcome in sAML patients. Methods The karyotypes of pre-treatment blast cells from previously untreated sAML patients on a phase II study were reviewed to identify categories of core binding factor karyotype (CBF), normal karyotype (CN), MK+ and MK- (as defined above), and compared to clinical outcomes. Patients on the study all received induction therapy with amonafide 600 mg/m2/day IV days 1-5 and cytarabine 200 mg/m2/day IV days 1-7. Consolidation consisted of stem cell transplant (HSCT, n=10) or intermediate-dose (IDAC, n=13)/high-dose (HiDAC, n=7) cytarabine, depending on age and available HSCT donors. Results 88 patients were treated. 2/88 (2%) were CBF, 29/88 (33%) were CN, 16/88 (18%) were MK+ and 31/88 (35%) were MK-. Patients with CBF and the 10 patients with unknown karyotype at baseline were excluded from the analysis. CR+CRi rate by karyotypic group was 19/29 (66%) for CN, 11/31 (35%) for MK-, 2/16 (13%) for MK+ (CN vs MK- p Conclusions In this study of 88 patients with secondary AML, a monosomal karyotype was predictive of inferior response to therapy compared with both a normal karyotype and a non-monosomal “unfavorable” karyotype. Importantly, the 2-year overall survival in the MK+ group was significantly inferior to that in the CN group. Of note durable complete remissions were observed in responders regardless of karyotype. Though the number of patients in this study is relatively small, to our knowledge this is the only prospectively defined study of sAML patients demonstrating a significantly adverse impact of monosomal karyotype as compared with other “unfavorable” karyotypes. Further data to address the prognostic and predictive significance of specific cytogenetic abnormalities in sAML will be obtained from a currently enrolling 450-patient phase III randomized trial of amonafide + cytarabine vs daunorubicin + cytarabine in patients with sAML (ACCEDE). Disclosures: Downie: Antisoma: Research Funding. Erba:Lilly: Research Funding; Antisoma: Research Funding; Wyeth: Research Funding; Cephalon: Honoraria, Research Funding; MGI Pharma: Honoraria; Pharmion: Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding. Stone:Celgene: Consultancy, Speakers Bureau; Merck: Consultancy; Genzyme: Consultancy; Eisai: Consultancy. Rizzieri:Antisoma: Research Funding. Foran:Antisoma: Research Funding.

Abstract 4159 Aurora kinases (AK) A and B are overexpressed in a proportion of patients with acute myeloid leukemia (AML) and the level of overexpression correlates with their sensitivity to AK inhibition in vitro. We recently reported data from a dose escalation study of AT9238, a small molecule inhibitor of AKs in patients with refractory leukemias in which eight of 24 AML patients with relapsed/refractory AML achieved a 3 33% reduction in bone marrow blasts and haematological improvement. All patients had received at least one line of previous therapy. Further analysis has revealed that of the eight patients with relapsed/refractory AML that benefited from treatment with AT9283 five had a normal karyotype and the remaining three patients showed evidence of isolated abnormalities of chromosome 7, including 7q loss. Separately, we have reported that AT9283 inhibits the proliferation and survival of AML cell lines in vitro and suggested that those cell lines with complex karyotypic abnormalities responded differently from normal diploid lines. In these experiments AML cell lines exhibit one of two phenotypes following exposure to AT9283; rapid induction of cell death at low nM concentrations (Phenotype 1) or endo-reduplication followed by cell death at a later time point (Phenotype 2). In both scenarios treatment with AT9283 results ultimately in cell death. Cell lines with a normal karyotype tended to undergo rapid apoptosis without evidence of endoreduplication at low concentrations of AT9283. These findings provide further support for the potential importance of karyotype as a determinant of outcome in the clinical study. This is the first indication that cytogenetics might be used to predict responsiveness to Aurora kinase inhibitors in the clinic. Disclosures: Lyons: astex therapeutics: Employment. Squires:Astex Therapeutics, Ldt: Employment. Goodall:astex therapeutics: Employment. Yule:Astex Therapeutics Ldt: Employment. Ravandi:BMS: Consultancy, Honoraria, Research Funding.

Abstract 1954 Poster Board I-977 Introduction: Despite advances in treatment and a well-characterized prognostic index, significant heterogeneity remains in DLBCL survival. Preliminary data suggest a potential survival disparity based on race/ethnicity or socioeconomic status (SES). To evaluate the impact of these and other variables on survival we performed an analysis in the ethnically diverse population-based California Cancer Registry (CCR). We utilized Neighborhood SES, an index of 7 census measures of education, income, occupation & cost of living, based on the residential census-block group at diagnosis. Each census-block group comprises ∼1500 residents. Neighborhood SES has been shown to be significantly associated with survival after Follicular Lymphoma (JCO 27:3044, 2009). Methods: All pts with DLBCL (ICD-O-3 codes 9680 & 9684) diagnosed from Jan 1988 to Dec 2007 and reported to CCR were included in the analysis, including n=16,892 diagnosed from 1988-2000, and n=11,916 from 2001-2007 (total study pop'n =28,808). HIV/AIDS pts were excluded, as were n=63 with Mediastinal LBCL & n=10 with primary effusion lymphoma. The mean age was 63 yrs, and the cohort was 53% male. Between time periods, there was a relative increase in Hispanic pts [15.4% (1988-2000) to 20.8% (2001-2007), p To evaluate the impact of prognostic factors (particularly diagnosis period, SES, and race/ethnicity) on overall survival (OS) & disease-specific survival (DSS) we used Cox proportional hazards regression to calculate hazard ratios (HR) for death with 95% CI's. Multivariate regression models included variables significant at p Results: There was a significant improvement in OS in patients diagnosed after 2001 for both LocReg (HR 0.87, 95%CI 0.82-0.91, p60 years was associated with a significantly worse OS for LocReg (HR 3.06, 95%CI 2.90-3.24) and ADV stage (2.02, 95%CI 1.93-2.12). Females also had significantly better OS compared with males (Loc-Reg - HR 0.90, 95%CI 0.86-0.94; ADV - HR 0.89, 95%CI 0.85-0.93). There was no significant impact of race/ethnicity on survival with the exception of non-Hispanic Asian/Pacific Islanders (NH A/PI) with ADV stage, for whom OS was significantly inferior compared with whites (HR 1.18, 95%CI 1.09-1.27, p Compared with the highest quintile (SES-5), there was a significant effect of lower neighborhood SES on OS and DSS (see Table). Conclusion: There has been a significant improvement in survival after DLBCL since 2001, but patients in the lowest SES-1 quintile have a 34% higher risk of death from any cause and 20% higher risk for death from lymphoma than those in the highest SES-5. In this model, race/ethnicity did not have a significant impact on survival with the exception of NH A/PI with ADV stage. Studies to understand and address these socioeconomic disparities are urgently required in order to extend the improvements in DLBCL survival more effectively. Disclosures: Foran: Genentech: Honoraria, Research Funding.

Abstract 584 Background: CMC-544 is a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. CMC-544 targets CD22, which is expressed in the majority of B cell non-Hodgkin lymphomas (NHL). The maximum tolerated dose (MTD) for single agent CMC-544 was previously determined to be 1.8 mg/m2administered IV every 28 days, and clinical activity was shown in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Preliminary safety and efficacy data without long-term follow-up on patients with FL and non-refractory DLBCL treated with CMC-544 given in combination with rituximab was previously reported. Objectives: To assess clinical activity of CMC-544 in combination with rituximab in refractory ‘aggressive' NHL and to present long-term follow-up, including progression free survival (PFS) and overall survival (OS) of pts with relapsed FL and DLBCL. Patients and Methods: Patients were eligible if they had CD20+/CD22+ B cell NHL, which had not responded to or progressed after 1 or 2 therapies of probable clinical benefit, including at least 1 regimen containing rituximab. In patients with FL and DLBCL, subjects could have had no more than 2 prior therapies and could not be refractory to rituximab or a rituximab-containing therapy. Patients in the latter part of the study could have DLBCL, mantle cell lymphoma, transformed FL with no limit on number of prior therapies and must have had no response to, or relapse within 6 months of, the first dose of the previous rituximab-containing therapy (refractory ‘aggressive' lymphoma). After a limited dose-escalation to determine the MTD of CMC-544 in combination with rituximab, an expanded cohort at the MTD was conducted. Patients received 375 mg/m2 of rituximab IV on day 1 followed by CMC-544 on day 2 of each 28-day cycle for up to 8 cycles, provided that there was no disease progression. Results: The MTD of CMC-544 given with rituximab was confirmed as the single agent dose of 1.8 mg/m2. Enrollment is complete at 119 patients, with 110 treated with CMC-544 at the MTD of 1.8 mg/m2. Based on 112 patients, median age was 66 y (range: 20-85), 60% were male; 36% had 1 prior chemo/immunotherapy regimen, 46% had 2, and 13% had ≥3; 71% had stage III/IV disease, 38% elevated LDH, and 17% bulky disease (>7.5 cm). Patients with recurrent DLBCL were generally older, with a median age of 72 y and were thus deemed inappropriate for high-dose therapy. The most common treatment-emergent adverse events (AEs), all grades, were nausea (48%), thrombocytopenia (46%), fatigue (44%), and increased aspartate aminotransferase (AST) (34%). AEs resulting in discontinuation from treatment were most commonly hematologic AEs or elevation of ≥1 liver function test. Median follow-up is approximately 14.5 months, 10.3 months, and 2.5 months for patients with FL, recurrent DLBCL, and refractory ‘aggressive' lymphoma, respectively. The 1-year OS rate was 97% for FL and 77% for patients with recurrent DLBCL. Patients with FL (n=38) had an objective response rate (ORR) of 87%, with a median PFS of 23.6 months. Patients with relapsed DLBCL (n=40) had an ORR of 80%, with a median PFS of 15.1 months while in the rituximab-refractory pt arm (n=25) the response rate was much lower at 20%, with a median PFS of only 2 months. One year PFS was 84% for FL and 53% for recurrent DLBCL. The lower response rates and PFS in the refractory subgroup are consistent with the poor prognosis of patients with refractory 'aggressive' lymphoma. PFS in DLBCL (either de novo or from transformed follicular) with 1-2 prior therapies based on time-to-tumor progression was also analyzed. DLBCL patients with a prior time to tumor progression of less than 1 year (n=19) had an ORR of 47% (21% CR/CRu), with a median PFS of 4.3 months while DLBCL patients with a prior time to tumor progression of greater than 1 year (n=28) had an ORR of 79% (50% CR/CRu) and a median PFS of 15.1 months. Conclusion: The combination of inotuzumab ozogamicin (CMC-544) plus rituximab has a safety profile similar to that previously reported for CMC-544 alone, with hematologic, gastrointestinal, and hepatic AEs being the main toxicities. The response rates and PFS results indicate promising efficacy in patients with recurrent/refractory FL and DLBCL, These results, particularly in patients with follicular lymphoma and recurrent DLBCL, support continued clinical development of this regimen. Disclosures: Dang: Wyeth Research: Consultancy; Genentech: Consultancy, Honoraria, Speakers Bureau; Biogen: Consultancy, Speakers Bureau. Smith:Millennium: Research Funding; Genentech: Research Funding; Wyeth Research: Consultancy, Research Funding. Johnson:Wyeth Research: Membership on an entity's Board of Directors or advisory committees. Kaufman:Millenium: Consultancy; Genzyme: Consultancy; Celgene: Consultancy, Research Funding; Merck: Research Funding. Coiffier:Wyeth Research: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Czuczman:Wyeth Research: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees. Foran:Wyeth Research: Research Funding. Hua:Wyeth Research: Employment. Vandendries:Wyeth Research: Employment, Equity Ownership. Fayad:Wyeth Research: Consultancy, Research Funding.

To the Editor: We write to report the development of peripheral T-cell lymphoma following therapy for B-cell lymphoma with the monoclonal antibody anti-CD20 (Rituximab) in the trial recently published in Blood .[1][1] The patient was a 59-year-old man of Anglo-Asian extraction who presented in 1992

Recent reports suggest that Aurora kinases (AK) A and B are overexpressed in a proportion of patients with AML and that the level of overexpression correlates with their sensitivity to AK inhibition in vitro. Inhibition of AKB results in mitotic exit in the absence of cell division resulting in polyploidy whilst AKA is responsible for the fidelity of mitotic spindle assembly and phosphorylates p53 at Ser315 leading to its ubiquitination by Mdm2 and subsequent proteolysis. Inhibition of this process increases p53 stability inducing cell-cycle arrest with 4N DNA. Clinical studies of the dual AK inhibitor AT9283 indicate that it is active in the treatment of a proportion of patients with relapsed/refractory AML. In order to explore the molecular basis of this varied sensitivity we investigated the effect of AT9283 in a panel of 10 AML cell lines from a variety of genetic backgrounds including a proportion driven by ras, Flt3 or c-kit mutations. Two phenotypes were observed; Accumulation of cells in the G2/M phase (4N) of the cell cycle followed by apoptosis, or Accumulation of cells with >4N DNA (polyploid) followed by apoptosis. Cell lines that exhibit the former phenotype were those driven by mutation in an oncogenic kinase such as ras, c-kit or Flt3. Further analysis of Cyclin B levels suggest that profile 1) results from a G2 block occurring as a consequence of a dominant AKA inhibitory effect in these cell lines. Profile 2) results from AKB inhibition; where cells continue to undergo rounds of DNA replication in the absence of cell division. Inhibition of both of these signaling pathways has been confirmed in AML blasts taken from patients treated with AT9283 in the ongoing clinical program. These results suggest that AT9283 triggers the mitotic checkpoint and induces apoptosis in patients harboring mutations in FLT3 or c-kit via AKA inhibition. These AML cases have been shown to be more likely to exhibit normal cytogenetics and this profile may be important in sustaining rapid peripheral blast proliferation typical of this subtype of AML. Cell lines that respond to treatment with AT9283 by becoming polyploid may be manifesting the effect of predominant AKB inhibition. The balance between these outcomes may reflect the corresponding levels of expression of AKA and AKB in individual subtypes of AML along with factors such as TP53 mutation being associated with genomic instability supporting the development of complex karyotypic abnormalities. Such preliminary findings indicate that patients with mutations in oncogenic signaling pathways may be particularly sensitive to treatment with AT9283 due to the presence of an intact mitotic checkpoint and a dominant Aurora A inhibitory phenotype. This hypothesis is currently being explored through the analysis of biological studies obtained from the ongoing clinical program.

Activating mutations in the receptor tyrosine kinase FLT3 are present in approximately 30% of patients (pts) with acute myeloid leukemia (AML), and they have a significantly worse prognosis than pts with wild type (WT) FLT3, suggesting that the activated kinase is a driver of the disease and a potential target for kinase inhibitor therapy. AC220 is a novel 2nd generation class III receptor tyrosine kinase (RTK) inhibitor with potent in vitro and in vivo activity in FLT3-dependent tumors. It is highly selective for WT and mutant FLT3 and several other class III RTKs, including KIT, CSF1R, RET and PDGFR. AC220 is in a first-in-human phase 1 study for relapsed or refractory AML pts, unselected for FLT3 mutations. The study has a standard 3+3 dose escalation design with 50% dose increments. AC220 is administered once daily as an oral solution for 14 days followed by a 14 day rest period (1 cycle) with a starting dose of 12 mg. Concurrently, pts are being dosed on a continuous dosing regimen starting at 200 mg/day for 28 days (1 cycle). Pts with clinical benefit may continue to receive further cycles. Currently, 52 pts have been dosed with AC220 up to 450 mg/day (10 dose cohorts). Median age was 60 yrs (range, 23 to 86 yrs), median number of prior therapies was 3 (range, 0 to 8) and 2 pts had prior allogeneic hematopoietic stem cell transplant (HSCT). Two elderly patients (age ≥ 78 yrs) unfit for induction chemotherapy were previously untreated. Fifteen patients have FLT3 mutations (12 ITD and 3 TKD), 25 are WT, and 12 are undetermined. Pts are also evaluated for PK, pFLT3, pSTAT5, FLT3 genotyping and ex vivo plasma inhibitory activity. AC220 is well tolerated and MTD has not yet been observed with either schedule. One pt had a possibly drug-related DLT in the 18 mg cohort (grade 3 CHF, although pt had a pre-existing heart condition) leading to cohort expansion, but no other cases of drug-related CHF or other DLT have been seen. Other possibly drug-related AEs (most frequently gastrointestinal events) were mild (grade ≤ 2). Response data based on investigator’s assessment are available on the first 45 pts. Responses were observed in 11 (24%) pts. Four pts achieved a complete response (CR) – 2 with incomplete platelet recovery (CRp) and 2 with incomplete platelet and neutrophil recovery (CRi), one of these pts also had complete resolution of leukemia cutis. In addition, 7 pts had partial responses (PR, defined as a decrease of ≥ 50% blasts to levels of 5%–25% in the bone marrow). Most responses (8/11, 73%) occurred after cycle 1 and one was observed after cycle 3. Median duration of response is 18 weeks (range, 4 to 26+ weeks). Three responders are FLT3 mutants (2 ITD and 1TKD), 5 are WT, 3 are undetermined. Six of the 9 non-responding pts with ITD mutations had initial rapid clearing of peripheral blasts with intermittent AC220 dosing, but subsequently progressed or had disease-related mortality. All these pts had aggressive disease and received a median of 6 prior treatment regimens (range, 3 to 8). AC220 plasma exposure is sustained between dose intervals and continues to increase in a dose-proportional manner from 12 mg to 300 mg. FLT3 phosphorylation is strongly suppressed when plasma obtained from study pts is tested ex vivo in FLT3-ITD and WT cell lines at 12 mg and 60 mg doses, respectively. Assessments of pFLT3 and pSTAT5 from treated pts’ peripheral blood are ongoing and will be presented. Encouraging preliminary efficacy results and an acceptable safety profile warrants continued evaluation of AC220 as a single agent and in combination with other therapeutics for the treatment of AML.

2518 Background: AT9283 inhibits aurora kinase A and B and targets other tyrosine and serine/threonine kinases associated with myeloid cell proliferation. Exposure of leukemia cell lines to AT9283 in vitro induces an “aurora inhibitory” phenotype with creation of large aneuploidal cells with limited replication potential which ultimately undergo mitotic catastrophe and apoptosis. Methods: AT9283 was administered by 72-hour IV continuous infusion (IVCI) to pts with refractory AML, ALL, high risk MDS, and imatinib- and dasatinib-refractory CML. A 3+3 dose escalation phase I design was employed to determine MTD and biological activity, and standard DLT definitions were employed. Results: A total of n=29 patients (med. age 54 years, range 22 to 86; 15M/14F) have been treated at 8 different dose levels: 3 (n=3 pts); 6 (n=3); 12 (n=7); 24 (n=3); 48 (n=4); 72 (n=3); 108 (n=3); and 162 (n=3) mg/m2 daily x 3. Median number of prior treatments was 2 (range 1–5); n=3 pts had prior allografts. Biological activity was...

AT9283 is a small molecule inhibitor of aurora kinases A and B, JAK2, and JAK3 (IC50

Background: Despite the existence of well-established clinical prognostic indices for diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), the 2 most common subtypes of NHL, significant heterogeneity in survival remains even within prognostic groups. SES has not previously been evaluated as a prognostic factor for NHL, particularly using an unselected patient population. We therefore used the large multiethnic CCR to examine NHL survival according to histology, race/ethnicity and neighborhood SES. Methods: NHL pts were identified from the CCR for the period 1988–97 using standardized ICD-0-3 classifications (morphology codes 9690–99 for FL & 9680–84 for DLBCL). Patients with evidence of HIV/AIDS were excluded. Neighborhood SES was assigned based on the address of residence at diagnosis, according to 1990 US Census Bureau census block group (each block contains about 1500 residents), and is based upon principal components of 7 indicator variables of SES (education level, proportion with blue collar job, proportion unemployed, median household income, proportion below 200% of poverty line, median rent & median home value). Using this index, we assigned each patient into an SES quintile (SES-1 lowest, SES-5 highest) based on the statewide distribution of neighborhood SES. We computed 5-year relative survival ± standard error (SE) with SEER*Stat software using customized race and SES-specific life tables based on US Census Bureau estimates for California residents. Results: Unselected DLBCL pts [n=13,604; comprising 73% non-Hispanic White (W), 4% Black (B), 14% Hispanic (H), 8% Asian/Pacific Islander (A)] & FL pts (n=7372; 82% W, 3% B, 11% H, 4% A) were identified. The overall 5 yr relative survival for DLBCL was 45.5% (SE 0.5) and for FL was 71.1% (SE 0.6); females had a better survival than males for DLBCL [F 48.3% (SE 0.7) vs. M 42.3% (SE 0.6)] but not for FL. Lower SES was associated with inferior survival for both DLBCL & FL (Table 1). Within SES groups there were not significant racial/ethnic differences in survival. However, in DLBCL, B (34%) and H (33%) pts were proportionally more likely to be in SES-1 than W (9%) or A pts (15%), and less likely to be in SES-5 (9% B, 10% H) than W (27%) or A (22%) pts. Similarly, in FL, B (39%) & H (26%) pts were also more likely than W (8%) & A (10%) pts to be in SES-1 and less likely to be in SES-5 (W-29%, A-32%, B-10%, H-11%). Conclusion: SES predicts survival in DLBCL and FL. Race/ethnicity differences in SES distribution are apparent in NHL patients, but when stratified by SES, race/ethnicity does not appear to predict for significant differences in NHL survival. 5 Year Relative Survival in DLBCL & FL by SES & Race SES-1 (%) SE (%) n SES-5 (%) SE (%) n W-non-Hispanic White; A-Asian/Pacific Islander; B-Black; H-Hispanic DLBCL 40.6 1.3 1905 49.4 1.0 3192 W 38.4 1.9 915 49.4 1.1 2701 A 44.0 4.2 168 48.2 3.5 244 B 45.0 4.2 185 54.3 7.3 51 H 41.6 2.1 637 48.9 4.0 196 FL 66.4 2.1 823 76.6 1.2 1959 W 66.3 2.7 502 77.1 1.2 1753 A 65.4 10.0 30 72.0 5.0 93 B 69.1 6.5 85 76.1 10.0 22 H 65.9 3.8 206 71.8 5.4 91

Background: As MCL has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate,90Y-ibritumomab tiuxetan (90Y-RIT), following 4 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction. Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr with measurable/evaluable disease and adequate organ function were eligible. At 4–8 weeks after 4 cycles of R-CHOP, responding (CR/PR) and stable pt received 0.4 mCi/kg 90Y-RIT. The primary endpoint was failure-free survival (FFS) and secondary objectives were evaluation of response and toxicity after R-CHOP and after 90Y-RIT. The study design required 52 eligible pt to demonstrate a prolongation of FFS by 50% compared with R-CHOP alone (median FFS 16 mo, Howard et al., JCO20:1288, 2002). Results: The characteristics of 56 eligible pt are: 73% male, median age 61 (33–83) yrs, 91% stage III/IV, 68% >1 extranodal site, 78% marrow-positive. IPI was 0–2 in 51%, 3–5 in 49%. Fifty-one (91%) pt received all treatment and best response (n=50) was 42% CR/CRu, 32% PR, 12% stable and 4% unevaluable, with an improvement in response in 16 pt after 90Y-RIT. After 90Y-RIT, 55% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 22/23 pt. Median follow-up (all pt) is 24.4 months. Median FFS for all 56 pt is 27 months with an estimated 71% FFS and 93% overall survival at 18 months. Among pt who completed all treatment and have been followed ≥1.5 yr (n=45), 33 remain failure-free and 12 have progressed (4 dead). Conclusions: 90Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. These data suggest prolongation of FFS over that expected with R-CHOP alone. Consolidation of remission in MCL with 90Y-RIT shows potential as a strategy to prolong remission duration and is applicable to most pt with MCL. However, longer follow-up in needed to evaluate the durability of remissions achieved.

Background: Despite a lower incidence of non-Hodgkin’s lymphoma (NHL) and specifically diffuse large B-cell lymphoma (DLBCL), the most common histologic subtype, previous studies suggest that blacks have a higher disease-specific mortality from NHL than whites. To study this disparity, we looked at the impact of race, treatment delays and the use of rituximab on survival in NHL and DLBCL. To control for access to care, we focused on a population of patients with Medicare benefits. Methods: After establishing a SEER-Medicare Data-Use Agreement and obtaining IRB approval, we used the linked SEER-Medicare database for NHL patients diagnosed from 1995 through 2002, with claims data through 2003. Multivariable logistic regressions were used to assess the difference between race and rates of survival, NHL histology, and the likelihood of receiving treatment within 90 days and of receiving rituximab at any time during the course of NHL treatment. Results: Among 41,704 NHL cases, 35,014 (85%) cases were in whites and 2,287 (5.5%) were in blacks. Of the 14,831 total cases of DLBCL, 12,449 (84%) were in whites and 715 (4.8%) were in blacks. Despite a lower incidence of NHL, blacks had a lower 1-year survival for NHL compared to whites (OR 0.68 [95% CI 0.61–0.76]). Blacks also had a lower 1-year survival for DLBCL compared to whites (OR 0.63[95% CI 0.53–0.75]). Patients treated within 90 days of diagnosis had improved 1-year survival for NHL (OR 1.10 [95% CI 1.03–1.18]) and for DLBCL (OR 1.60 [95% CI 1.47–1.75]). When controlling for age, gender and income, blacks were less likely than whites to be treated within 90 days of a NHL diagnosis (OR 0.599 [95% CI 0.526–0.681]). The use of rituximab was associated with improved 1-year survival for NHL (OR 3.67 [95% CI 3.37–4.00]) and specifically for DLBCL (OR 3.01 [95% CI 2.66–3.40]). However, blacks were significantly less likely to receive rituximab for NHL (OR 0.55 [95% CI [0.47–0.63]) and specifically for DLBCL (OR 0.71[95% CI 0.57–0.90]). An analysis of two and three year survival for NHL and DLBCL yielded similar results for the impact of race, treatment delays and use of rituximab. Conclusions: Blacks are diagnosed with NHL and specifically DLBCL less frequently than whites but have significantly lower 1-year survival rates. Blacks were significantly less likely to begin treatment within 90 days of a NHL diagnosis. In addition, blacks were significantly less likely to receive rituximab despite presumed equal access to healthcare with Medicare benefits. The reason for this racial disparity is unclear. Studies to further characterize the disparity are needed.

Chemotherapy-induced neutropenia can cause complications that result in dose reductions or treatment delays that can, in turn, compromise clinical outcomes. Although the prophylactic use of colony-stimulating factors (CSFs) can reduce the risk, severity, and duration of severe and febrile neutropenia, they are not routinely administered to all patients undergoing myelosuppressive chemotherapy because of the costs. Selective use may, however, enhance their cost-effectiveness. These guidelines discuss the preventative or prophylactic use of recombinant human granulocyte-CSF to reduce the incidence, length, and severity of chemotherapy-related neutropenia and and prevent life-threatening complications. For the most recent version of the guidelines, please visit NCCN.org

Introduction: CMC-544 is an antibody-targeted chemotherapy agent composed of a humanized antibody that specifically targets the CD22 antigen, conjugated to calicheamicin, a potent cytotoxic antitumor agent. Malignant cells of mature B-lymphocyte lineage express CD22, suggesting that CMC-544 may be useful for treating lymphomas of B-cell origin. A phase 1 dose-escalation trial of CMC-544 was performed at 14 European and US sites with 36 patients in the dose escalation portion and 48 in the expanded MTD portion. The MTD dose was 1.8 mg/m2 every 4 weeks. In the dose escalation phase the main toxicities observed were thrombocytopenia, asthenia, nausea, neutropenia, elevated liver function tests (LFTs) and anorexia. Grade 3–4 levels were only seen for thrombocytopenia, asthenia, neutropenia and LFTs (incidence of 40%, 13%, 9% and 9% respectively). Responses were seen in 8/22 (36%) patients (Advani A, et. al. Blood, abstract# 230, 2005:106). We now report the results of the expanded cohort at the MTD. Patients and Methods: Relapsed/refractory lymphoma patients were treated at the 1.8 mg/m2 dose level every 4 weeks. In addition to safety data, preliminary efficacy data (assessed using the International Workshop to Standardize Response Criteria for NHL) were collected. Results: As of July 2006, 48 patients were treated: median age 57 years (range 26–75); 51% females; 61% with ≥ 4 prior lines of therapy; 22 (46%) follicular lymphomas (FL) and 26 (54%) diffuse large B-cell lymphomas (DLBCL). Data were available on 48 patients evaluable for safety and 34 patients (19 FL and 15 DLBCL) evaluable for response. The overall safety profile was manageable; the most common drug-related adverse events (all grades) included thrombocytopenia (90%; the only bleeding noted was grade 1–2 epistaxis [12%]), asthenia (57%), nausea (39%), neutropenia (37%) and elevated levels of AST/SGOT (41%), ALT/SGPT (18%), alkaline phosphatase (27%) and bilirubin (18%). Grade 3–4 AEs that occurred with a frequency ≥ 10% included thrombocytopenia (57%) and neutropenia (29%). Responses in evaluable patients are shown in Table 1. The objective response rate was 69% and 33% for patients with FL and DLBCL, respectively. Conclusions: CMC-544 exhibits effficacy against recurrent/refractory B-cell lymphomas, with the main toxicity being clinically manageable, self limited thrombocytopenia. These encouraging data support the continuing development of CMC-544. Number (%) of Responses in Evaluable Patients: Response Follicular Lymphoma (n=19) DLBCL (n=15) ORR = Overall Remission Rate, (CR/CRu+PR) CR/CRu 6 (31.7) 2 (13.3) PR 7 (36.8) 3 (20.0) ORR 13 (68.5) 5 (33.3)

7503 Background: Because mantle cell lymphoma (MCL) has a continuous relapse pattern with current treatments, we designed a study to determine the safety and efficacy of the anti-CD20 radio-immunoconjugate,90Y-ibritumomab tiuxetan (90Y-RIT), after R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) induction. Methods: Patients (pt) with untreated stage II-IV MCL (CD20+, cyclin D1+) ≥18 yr were eligible if they had measurable/evaluable disease, adequate organ function (WBC >2,500/μl; platelets >100,000/μl unless marrow-positive) and gave informed consent. At 4–8 weeks after 4 cycles of R-CHOP, stable and responding pt meeting standard marrow and hematologic criteria received 0.4 mCi/kg 90Y-ibritumomab tiuxetan. Objectives were to evaluate response and toxicity after R-CHOP and 90Y-RIT with a primary endpoint of time to treatment failure (TTF). Results: 56 of 57 accrued patients are eligible pending central pathology review. Characteristics included 73% male, median age 60 (33–83) yrs, 91% stage III/IV, 64% >1 extranodal site, 75% marrow-positive. IPI was 0–2 in 50%, 3–5 in 43% and unknown in 7%. After 90Y-RIT 53% had grade 3/4 neutropenia with no febrile neutropenia and 45% had grade 3/4 thrombocytopenia with recovery at 12 weeks in 19/20 pt. 50 pt are evaluable for response after R-CHOP and 44 pt after 90Y-RIT. Best response after R-CHOP (n = 50) was: CR/CRu 14% (n = 7), PR 58% (n = 29), SD 26% (n = 13), PD 2% (n = 1). After 90Y-RIT, responses improved in 15 of 37 pt with 90Y RIT after 4 cycles of R-CHOP in untreated MCL is safe and improves the number and quality of responses. Further follow-up is needed to determine TTF. [Table: see text]

The myelodysplastic syndromes (MDS) represent myeloid clonal hemopathies with relatively heterogeneous spectrums of presentation. The major clinical problems in these disorders are morbidities caused by patients' cytopenias and the potential for MDS to evolve into acute myeloid leukemia (AML). Managing MDS is complicated by the generally advanced age of the patients (median ages range from 65–70 years), the attendant non-hematologic comorbidities, and older patients' relative inability to tolerate certain intensive forms of therapy. In addition, when the illness progresses into AML, these patients experience lower response rates to standard therapy than patients with de novo AML. For the most recent version of the guidelines, please visit NCCN.org

Despite significant advances in the treatment of acute myeloid leukemia (AML) in younger adults, there has been little progress in the treatment of older patients (age≥60 years), who comprise the majority of those with the disease. Clofarabine is a purine nucleoside analog with single agent activity in patients with relapsed AML. In addition, clofarabine potentiates Ara-C cytotoxicity in vitro through increased intracellular Ara-CTP accumulation, making this an attractive combination. A phase I/II study has therefore been initiated combining clofarabine with standard dose cytarabine (100mg/m2/day x 7) in pts age ≥60 years with de novo AML. The starting dose of clofarabine was 30mg/m2/day x 5 beginning on day 2 (Dose level I). Patients were accrued in cohorts of 3–6 to establish dose limiting toxicity (DLT); cohort expansion at the maximum tolerated dose (MTD) is planned in phase II using a Simon 2-stage design. Detailed plasma and intracellular pharmacokinetics were performed during induction therapy with Ara-C alone (day 1), and following the addition of clofarabine (day 2) to determine the effect of clofarabine on intracellular Ara-CTP accumulation. Pts with residual AML on d14–21 restaging bone marrow (BM) biopsy were eligible to receive Re-Induction with 5 days of clofarabine & Ara-C. Those achieving complete remission were also eligible to receive 1–2 cycles of consolidation with Ara-C (d1–5) & clofarabine (total 3 cycles of planned therapy). Dose limiting toxicity was encountered at dose level I (see Table 1). 2/4 pts achieved CR, in 1 case with residual cytogenetic abnormality, and there were 2 treatment-related deaths from infxn (culture neg sepsis, n=1; Candida tropicalis, n=1). In the latter case (pt 4), BM aplasia was achieved, but the pt died on d25 prior to hematologic recovery. In view of the DLT, the protocol has therefore been amended to allow 25% dose de-escalation of clofarabine to Dose Level -I (22.5mg/m2/day x 5), and to limit eligibilty to pts age 60–75 yrs inclusive. Routine use of aggressive pre-hydration and antibiotic and antifungal prophylaxis is now mandated. Clofarabine & cytarabine is a highly active induction regimen in older adults age ≥60 yrs with de novo AML, but has significant myelosuppressive and infectious toxicity. The study is proceeding in phase I at Dose Level -I to establish the MTD. Phase I, Dose Level I PT AGE, GENDER FAB CYTOGENETICS F/U BM TOXICITY (Gr.III/IV) OUTCOME MLD - multilineage dysplasia; F&N - fever & neutropenia; CR - complete remission 1 66M M2 Diploid D21: residual AML renal, infxn Death 2 61M M2 Complex D14: aplastic F&N CR 3 69M M2 with MLD Intermediate Risk D21: recovering F&N CR 4 77F M2 Diploid D14: aplastic renal, infxn, capillary leak Death

PURPOSE: To evaluate the incidence of and risk factors for therapy-related myelodysplasia (tMDS) and secondary acute myelogenous leukemia (sAML), after high-dose therapy (HDT) with autologous bone marrow or peripheral-blood progenitor-cell support, in patients with non-Hodgkin’s lymphoma (NHL). PATIENTS AND METHODS: Between January 1985 and November 1996, 230 patients underwent HDT comprising cyclophosphamide therapy and total-body irradiation, with autologous hematopoietic progenitor-cell support, as consolidation of remission. With a median follow-up of 6 years, 27 (12%) developed tMDS or sAML. RESULTS: Median time to development of tMDS or sAML was 4.4 years (range, 11 months to 8.8 years) after HDT. Karyotyping (performed in 24 cases) at diagnosis of tMDS or sAML revealed complex karyotypes in 18 patients. Seventeen patients had monosomy 5/5q−, 15 had −7/7q−, seven had −18/18q−, seven had −13/13q−, and four had −20/20q−. Twenty-one patients died from complications of tMDS or sAML or treatment for tMDS or sAML, at a median of 10 months (range, 0 to 26 months). Sixteen died without evidence of recurrent lymphoma. Six patients were alive at a median follow-up of 6 months (range, 2 to 22 months) after diagnosis of tMDS or sAML. On multivariate analysis, prior fludarabine therapy (P = .009) and older age (P = .02) were associated with the development of tMDS or sAML. Increased interval from diagnosis to HDT and bone marrow involvement at diagnosis were of borderline significance (P = .05 and .07, respectively). CONCLUSION: tMDS and sAML are serious complications of HDT for NHL and are associated with very poor prognosis. Alternative strategies for reducing their incidence and for treatment are needed.

PURPOSE: To analyze the presentation features and outcome for patients with immunocytoma (IMC) managed at St Bartholomew's Hospital (SBH), London, United Kingdom, between 1972 and 1996. Outcome was compared with that of patients with small lymphocytic lymphoma (SLL)/B-cell chronic lymphocytic leukemia (B-CLL) treated at SBH during the same period. PATIENTS AND METHODS: One hundred twenty-six patients with newly diagnosed IMC were identified. Patients were subclassified (using the Kiel classification) as having lymphoplasmacytoid (n =92), lymphoplasmacytic (n = 24), polymorphous (n = 9), or undetermined (n = 1) IMC. Six patients (5%) had stage I to IIE disease; the rest had advanced disease. Treatment was given according to disease stage. Seven patients were managed expectantly. RESULTS: Eighty-two (69%) of 119 patients responded to treatment, but complete remission was seen in only 15 (13%) of 119. Treatment failed in 29 (24%) of 119 patients. There were three treatment-related deaths; five patients were not assessable for response. When survival of patients with IMC was compared with that of patients with B-CLL/SLL, a significant difference was found (P < .01); this difference was maintained when only patients in whom the diagnosis was based on lymph node biopsy were considered (P = .01). A comparison of the three IMC subgroups showed that there was a trend (P = .06) toward a difference between B-CLL/SLL and the lymphoplasmacytoid subtype. CONCLUSION: Patients diagnosed with IMC are generally older and present with advanced disease. Conventional therapies usually result in incomplete responses of short duration. Overall, these results support the proposed World Health Organization reclassification of IMC to include lymphoplasmacytoid lymphoma (Kiel classification) as a variant of B-CLL/SLL.

Ewing’s sarcoma and peripheral neuroectodermal tumor (PNET) are “small round blue cell tumors.” The majority of cases share the cytogenetic translocation t(11;22) (q24;q12), with occasional variations, and a characteristic immunohistochemical staining profile. 1–3 Both these tumors are believed to show neuroectodermal differentiation, albeit in different degree; Ewing’s sarcoma tends to be poorly differentiated, whereas PNET most often shows definite neuroectodermal differentiation. Although once viewed as distinct entities, Ewing’s sarcoma, Askin’s tumor, and PNET are now considered together as members of the Ewing family of tumors. 4,5 As such, they are increasingly grouped together for both treatment and prognostic factor analysis. 6–8 Ewing’s sarcoma/PNET has a marked propensity for systemic spread, and therefore intensive multiagent chemotherapy is the mainstay of treatment. Significant progress has been made in terms of defining active chemotherapy regimens, 9–12 and current multiinstitutional studies are underway to optimize these regimens. Local treatment usually consists of surgery, surgery plus radiation therapy, or radiation therapy alone. The relative efficacies of these local treatments remain controversial. Most patients with Ewing’s sarcoma/PNET are 10 to 20 years old, 13 and therefore there is a relative paucity of literature relating to outcome for adults with this disease of childhood and adolescence. Some early reports had suggested that adults with Ewing’s sarcoma/PNET have a less favorable outcome than children, 14,15 but a recent study of adult patients from the Royal Marsden Hospital in London has suggested that adults may have a similar outcome to children. 16 The objective of the current study was to evaluate the outcomes and assess prognostic factors for a population of adult patients with Ewing’s sarcoma/PNET seen at our institution.

The aim of this study was to determine whether administration of BB-10010, a synthetic stem cell inhibitor, would allow more intensive chemotherapy to be administered to patients with newly diagnosed high grade NHL. Thirteen patients were randomised to receive BB-10010 concurrently with dose-intensified BEMOP/CA chemotherapy (7 patients) or chemotherapy alone (6 patients). Although the mean neutrophil count of BB-10010 treated patients was higher following cycles 1, 2 and 3 of chemotherapy compared with those receiving chemotherapy alone, there was no difference in the mean number of cycles tolerated, blood component usage and hospital admissions due to infections. No specific toxicity of BB-10010 was identified. Whilst BB-10010 can be administered safely, it does not improve the ability of patients to tolerate intensive chemotherapy for high grade NHL.

Background Therapy and outcome for elderly acute myeloid leukemia (AML) patients has not improved for many years. Similarly, there remains a clinical need to improve response rates in advanced myelodysplastic syndrome (MDS) patients treated with hypomethylating agents, and few combination regimens have shown clinical benefit. We conducted a 5-azacytidine (5-Aza) RNA-interference (RNAi) sensitizer screen to identify gene targets within the commonly deleted regions (CDRs) of chromosomes 5 and 7, whose silencing enhances the activity of 5-Aza. Methods and results An RNAi silencing screen of 270 genes from the CDRs of chromosomes 5 and 7 was performed in combination with 5-Aza treatment in four AML cell lines (TF-1, THP-1, MDS-L, and HEL). Several genes within the hedgehog pathway (HhP), specifically SHH, SMO, and GLI3, were identified as 5-Aza sensitizing hits. The smoothened (SMO) inhibitors LDE225 (erismodegib) and GDC0449 (vismodegib) showed moderate single-agent activity in AML cell lines. Further studies with erismodegib in combination with 5-Aza demonstrated synergistic activity with combination index (CI) values of 0.48 to 0.71 in seven AML lines. Clonogenic growth of primary patient samples was inhibited to a greater extent in the combination than with single-agent erismodegib or 5-Aza in 55 % (6 of 11) primary patient samples examined. There was no association of the 5-Aza/erismodegib sensitization potential to clinical-cytogenetic features or common myeloid mutations. Activation of the HhP, as determined by greater expression of HhP-related genes, showed less responsiveness to single-agent SMO inhibition, while synergy between both agents was similar regardless of HhP gene expression. In vitro experiments suggested that concurrent dosing showed stronger synergy than sequential dosing. Conclusions Inhibition of the HhP with SMO inhibitors in combination with the hypomethylating agent 5-Aza demonstrates synergy in vitro and inhibits long-term repopulation capacity ex vivo in AML and MDS. A clinical trial combining 5-Aza with LDE225 (erismodegib) in MDS and AML is ongoing based on these results as well as additional publications suggesting a role for HhP signaling in myeloid disease. Electronic supplementary material The online version of this article (doi:10.1186/s13045-015-0211-8) contains supplementary material, which is available to authorized users.

PURPOSE: To assess the patterns of recurrence, management, and survival following recurrence after myeloablative therapy with autologous bone marrow transplantation (ABMT) in patients with follicular lymphoma (FL). PATIENTS AND METHODS: Between June 1985 and October 1995, 99 patients with FL received cyclophosphamide and total-body irradiation with ABMT as consolidation of second or subsequent remission. RESULTS: Median length of follow-up was 5½ years, and 33 patients developed recurrent lymphoma a median of 14 months after ABMT. In 26 patients, the recurrence was overt; in seven, it was detected on surveillance investigation. Twenty-six patients presented with recurrence at previous sites of disease. Twenty-two patients (67%) had FL at the time of recurrence; in 11 (33%), there was evidence of transformation to diffuse large B-cell lymphoma. Eight patients were managed expectantly; five were alive 21 to 53 months later. Twenty-five patients have required treatment to date; eight remained alive 6 months to 10 years later, and five were in remission. The Kaplan-Meier estimate of patients alive 5 years after recurrence is 45% (95% confidence interval, 27% to 62%). In univariate and multivariate analyses, survival after recurrence and overall survival after diagnosis were similar to those of a historical control group who received conventional treatment, before the introduction of myeloablative therapy (adjusted hazard ratio [HR], 1.56, P = .3, and HR, 1.34, P = .4, respectively). CONCLUSION: The survival pattern of patients with FL following recurrence after myeloablative therapy and ABMT suggests that this treatment does not compromise outcome in patients in whom it fails, reflecting the survival pattern of the disease when treated conventionally.

PURPOSE: Mantle-cell lymphoma (MCL), immunocytoma (IMC), and small B-cell lymphocytic lymphoma (SLL) are B-cell malignancies that express CD20 and are incurable with standard therapy. A multicenter phase II study was conducted to assess the toxicity and the overall response rates (RR) and complete response (CR) rates to rituximab (chimeric anti-CD20 monoclonal antibody). PATIENTS AND METHODS: Between January 1997 and January 1998, 131 patients with newly diagnosed MCL (MCL1; n = 34) and previously treated MCL (MCL2; n = 40), IMC (n = 28), and SLL (n = 29) received rituximab 375 mg/m2/wk for 4 weeks via intravenous infusion. Restaging studies were performed 1 and 2 months after treatment. An analysis of the duration of response was conducted in December 1998. RESULTS: Eleven patients were unassessable, including one who died of splenic rupture after the first infusion. The RR among the 120 assessable patients was 30% (36 of 120 patients). The RR by histology was as follows: MCL1, 38%; MCL2, 37%; IMC, 28%; and SLL, 14%. Ten patients, all with MCL, achieved CR. The median duration of response in MCL was 1.2 years. Immediate side effects were common and usually responded to adjustments in the infusion rate. There were 31 episodes of infection after treatment; most cases were mild. Cardiac arrhythmia and ophthalmologic side effects occurred in 10 and nine patients, respectively, including one case of severe loss of visual acuity. CONCLUSION: Single-agent rituximab has moderate activity in MCL and IMC but only limited activity in SLL. The duration of response in MCL was similar to that previously reported in follicular lymphoma. Its use in combination with cytotoxic chemotherapy to increase the CR rate is warranted in MCL and IMC.