Treatment Of Other Malignancies Research Articles

A Prognostic Score System for Survival in Secondary AML: Review of 1073 Patients Observed At MDACC

AbstractAbstract 131▪▪This icon denotes a clinically relevant abstract BackgroundSecondary Acute Myeloid Leukemia (sAML) is associated with prior treatment for other malignancies, particularly chemotherapy (Chemo) or radiation therapy (RT), and characterized by very bad prognosis due to high-risk features and poor clinical outcomes. Patients and MethodsWe identified 1073 patients (pts) at MDACC since March 1976 to Sept. 2011 with sAML, who were diagnosed with 1 (n=943), 2 (n=117), or 3 (n=12) Prior Malignancies (PM). Pts' characteristics, including age; type of PM; number and treatments for PM; and characteristics at sAML diagnosis such as % bone marrow and blood blasts, WBC, hemoglobin, platelet and neutrophil count, FAB, and karyotype were analyzed and correlated with survival outcome. A prognostic score for survival was developed using significant variables identified in multivariable analysis (MVA). ResultsMedian time to sAML was 64 months (mo) and 46 (p=0.000) for pts with 1 or >1 PM, respectively; longer for pts with untreated PM (62 vs 27, mo p=.008) and correlated with type of PM (p=0.001) and previous monotherapy (Surgery vs RT vs Chemo, p=.006). Median age at sAML was 66 years; 54% (n=574) were male; and pts had 1, 2 or 3 PM in 88, 11 and 1% cases, respectively. All FAB categories were represented. Median baseline characteristics at sAML were as follows: HGB 9 g/dL (2.6–17.5), PLT 49K/μL (1–1,518), WBC 4K/μL (.02–367.2), ANC 890/μL (0–84100), blood blasts 8% (0–99), and bone marrow blasts 40% (0–99). Type of prior malignancy reflected prior treatment: breast (21%), hematological (20%), prostate (14%), and skin (10%) were the most represented as 1st malignancies; 728 underwent prior surgery, 468 received prior RT, and 563 pts received prior Chemo alone or in combination, 40 pts were untreated for their PM. For pts with sAML who had only undergone prior surgery (n=310), favorable-, intermediate-, and poor-risk karyotype was reported for 9, 49, and 32%, respectively. Pts with sAML previously treated with RT only (n=72) had favorable-, intermediate-, and poor-risk karyotype in 8, 56, and 24% cases, respectively. Those who had previously received only Chemo (n=124) had favorable-, intermediate-, and poor-risk karyotype in 6, 21, and 57% cases, respectively. Univariable (UVA) and MVA analysis for survival are shown in the Table.We identified 3 survival risk-categories (Figure) according to a sum total score in which a point was given for each of the following significant variables identified in the MVA: PM Treatment (other than surgery), Age ≥60, Plt <50, Hgb <10, WBC ≥10, blood blasts >20%, and Kayotype int; 2 points was given for bad Karyotype. The estimated median OS was 58.6 (19.4, NA) mos for Group 1 (0–1 points), 13.9 (12.1, 16.2) mos for Group 2 (2–4 points), and 4.8 (4.1, 5.72) mos for Group 3 (5–8 points). ConclusionPatients diagnosed with sAML are high-risk for poor survival. Characteristics independently associated with short survival were identified and a prognostic score system was developed. Unfavorable karyotype remains a major factor associated with short survival. Validation of this model will come from prospective studies and additional insights should come from gene sequencing studies. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

PI3K/mTOR inhibition upregulates NOTCH-MYC signalling leading to an impaired cytotoxic response

PI3K, mTOR and NOTCH pathways are frequently dysregulated in T-cell acute lymphoblastic leukaemia (T-ALL). Blockade of PI3K and mTOR with the dual inhibitor PI-103 decreased proliferation in all 15 T-ALL cell lines tested, inducing cell death in three. Combined PI3K/mTOR/NOTCH inhibition (with a γ-secretase inhibitor (GSI)) led to enhanced cell-cycle arrest and to subsequent cell death in 7/11 remaining NOTCH mutant cell lines. Commitment to cell death occurred within 48-72 h and was maximal when PI3K, mTOR and NOTCH activities were inhibited. PI-103 addition led to upregulation of c-MYC, which was blocked by coincubation with a GSI, indicating that PI3K/mTOR inhibition resulted in activation of the NOTCH-MYC pathway. Microarray studies showed a global increase in NOTCH target gene expression upon PI3K/mTOR inhibition. NOTCH-MYC-induced resistance to PI3K/mTOR inhibition was supported by synergistic cell death induction by PI-103 and a small molecule c-MYC inhibitor, and by reduction of the cytotoxic effect of PI-103+GSI by c-MYC overexpression. These results show that drugs targeting PI3K/mTOR can upregulate NOTCH-MYC activity, have implications for the use of PI3K inhibitors for the treatment of other malignancies with activated NOTCH, and provide a rational basis for the use of drug combinations that target both the pathways.

Chronic Myelogenous Leukemia Following Treatment for Other Malignancies:A Single Institutional Experience

Chronic myelogenous leukemia (CML) secondary to treated primary malignancies is rare, and the literature is limited to few case reports. We analyze 5 cases of CML following therapy for primary malignancy. All cases of CML in the past 10 years were retrieved from our pathology database and were retrospectively evaluated. Of 67 cases of newly diagnosed CML, 5 (7.5%) had …

Factors associated with outcome of secondary MDS and AML: Review of 2,182 patients at MDACC.

6603 Background: Secondary acute myeloid leukemia (sAML) and myelodysplastic syndromes (sMDS) have been associated with prior treatment for other malignancies, particularly chemotherapy, and associated with high-risk features and poor clinical outcomes. Methods: We identified 2,182 patients (pts) (57% male) diagnosed with AML (n=1,073; all FAB/WHO represented) or MDS (n=1,109; 984 MDS, 125 MDS/MPD, all WHO represented) and who had 1 (n=1,907), 2 (n=239), or 3 (n=36) prior malignancies (PM). Pt characteristics and outcomes were analyzed. Results: The median age was 67 yrs. Prior hematological neoplasms (25%), breast (16%), prostate (16%), skin (9%) were most common. The prior malignancy reflected prior treatment, 1,252 pts underwent surgery, 939 received radiation, and 1,211 received chemotherapy alone or in combination; 124 were untreated. Types of prior malignancy and prior treatment associated with AML and MDS will be presented. Median time to AML/MDS was 64 months (mo) and 46 mo (p=0.000) for pts with 1 or &gt;1 PM, respectively, and correlated with type of PM (p=0.000) and previous monotherapy (surgery vs RT vs chemo) (p=0.020). For both AML and MDS, the incidence of poor-risk cytogenetics was nearly twice for pts who received prior chemotherapy compared to those who underwent surgery or radiation alone. Factors associated with survival in secondary AML and MDS are reported in the table. Conclusions: In conclusion, outcomes for pts with secondary AML and MDS are poor, especially for pts treated with prior chemotherapy. Type of prior malignancy and treatment are correlated with outcomes. Furthermore, greater number of prior malignancies correlates with inferior outcomes. [Table: see text]

MECHANISMS IN ENDOCRINOLOGY: Ipilimumab: a novel immunomodulating therapy causing autoimmune hypophysitis: a case report and review

Ipilimumab (Yervoy; Medarex and Bristol-Myers Squibb) is a human MAB against cytotoxic T-lymphocyte antigen 4, which enhances co-stimulation of cytotoxic T-lymphocytes, resulting in their proliferation and an anti-tumour response. It is licensed for the treatment of unresectable or metastatic malignant melanoma, while multiple clinical trials using this medication in the treatment of other malignancies are ongoing. As a clinical response to ipilimumab results from immunostimulation, predictably it generates autoimmunity as well, causing immune-related adverse events in the majority of patients. Of those, endocrinopathies are frequently seen, and in particular, autoimmune lymphocytic hypophysitis with anterior panhypopituitarism has been reported a number of times in North America. We present a case of a male referred to our department with manifestations of anterior panhypopituitarism after his third dose of ipilimumab for metastatic malignant melanoma, and we discuss the management of his case in the light of previous reports. We also review the published literature on the presenting symptoms, time to presentation, investigations, imaging, treatment and follow-up of ipilimumab-induced autoimmune lymphocytic hypophysitis.

Viral lymphomas: can antivirals be used to treat cancer?

Current knowledge suggests that EBV, KSHV and HTLV-1 contribute to lymphomagenesis by subverting the host-cell molecular signaling machinery to deregulate cell growth and survival. Some signaling pathways that are affected by these viruses are well characterized, such as the NF-kB pathway, which is activated by these three viruses to promote cellular survival by inhibiting apoptosis, thereby playing a critical role in tumorigenesis. Other pathways, such as MTOR and JAK-STAT are also likely involved in viral lymphomagenesis. This provides the opportunity to inhibit these cellular pathways using drugs developed for the treatment of other malignancies. However, since these compounds target cellular proteins, they always have the potential for toxicity. In the context of viral malignancies, we have the unique opportunity of targeting viral proteins, and developing completely specific therapies. Here we will examine the question of whether the pathobiology of EBV, KSHV and HTLV-1 will allow the use of such an approach.

Pertuzumab for the treatment of patients with previously untreated HER2-positive metastatic breast cancer

Pertuzumab is a humanized monoclonal antibody directed at the dimerization domain of the receptor tyrosine-protein kinase erbB-2 (HER2) receptor. It possesses a unique and complimentary mechanism of action compared to trastuzumab, which has historically been the cornerstone of therapy for HER2-amplified breast cancer. Clinical trials demonstrate improved outcomes, with minimal increases in toxicity with the addition of pertuzumab to trastuzumab in patients with HER2-positive metastatic breast cancer, indicating the advantage of dual HER2 receptor blockade. Pertuzumab is approved as first-line therapy in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer, with future opportunities to investigate its efficacy in other stages of breast cancer, as well as in the treatment of other malignancies.

Discontinuation of Imatinib in Patients with Chronic Myeloid Leukemia Who Have Maintained Complete Molecular Response: Update Results of the STIM Study

Abstract 603 Background:Imatinib treatment significantly improves survival in patients (pts) with CML. We previously demonstrated that Imatinib could be safely discontinued in pts with a complete molecular response (CMR) of at least 2 years duration and reported an interim analysis on 69 pts having at least 12 months of follow-up (FU) (Lancet oncology, 2010;11: 1029–1035). Little is known about whether treatment can safely be discontinued in the long term. The FU of this pt population is therefore crucial. Herein we aim to present the updated results from the first 100 pts included in the STIM study with a longer FU. Methods:In this multicentre, non-randomized Stop Imatinib (STIM) study, imatinib (of >2 years duration) was discontinued in CML pts with who were aged 18 years and older and in CMR sustained for at least 2 years. Pts that had undergone immunomodulatory treatment (apart from interferon α), treatment for other malignancies, or allogeneic haematopoietic stem-cell transplantation were excluded. Rate of relapse was assessed by use of RT-PCR and was defined as positivity of BCR–ABL transcripts in quantitative RT-PCR with a ratio of BCR–ABL to ABL of 0.001 or more, as confirmed by a second analysis point, indicating the increase (at least 1log) in relation to the first analysis point at two successive assessments. Quantitative RT-PCR for BCR–ABL transcripts from peripheral blood was performed every month during the first year and every 2 months thereafter. Beyond 2 years, molecular biology FU was performed every 3 months. Results:From July 9, 2007, to Dec 17, 2009, 100 pts (48 men, 52 women) with CML and a median age of 63 years (range 29–80) were recruited in the STIM trial. The median FU of the first 100 pts enrolled was 30 months (range 9–45) with a mean of 30 months. After imatinib was discontinued, a molecular relapse occurred in 61 pts with 58 relapses occurring during the first 7 months and 3 late relapses at month 19, 20 and 22, respectively. The overall probability of maintenance of CMR at 24 and 36 months was 39% (95% CI 29–48). We confirmed that all patients were sensitive to an imatinib re-challenge. Among the 61 with molecular recurrence, 56 regained CMR after imatinib re treatment. A median time of 4 months (range 0–21) was necessary for CMR to recur. Five pts did not return to CMR, 4 pts were continuously free of treatment with a median BCR-ABL level of 0.15% (0.05 to 0.3) at last evaluation and one received dasatinib due to a BCR-ABL level of 6.6%, i.e corresponding to a loss of a complete cytogenetic response. Among the 39 pts without confirmed molecular relapse, 5 exhibited clearly a fluctuation in BCR-ABL transcripts levels with a median FU of 22 months (6-35). Sokal risk group was available for 95% of pts and among the 11 pts with high sokal score 10 relapsed. The probability to be in stable CMR after discontinuation was significantly better for the low risk group (55% at 24 months, p<0.001) as compared to intermediate and high risk group. Using multivariate analysis, we confirmed that Sokal risk score (low vs intermediate vs high; p=0.0009) and Imatinib therapy duration (<60 months vs ≥60 months p=0.0183) were 2 independent prognostic factors for prediction of molecular relapse after imatinib cessation. Taking into account the cost of imatinib and the number of months without treatment in the total study population at last analysis, the savings within the STIM trial were estimated at 4 million Euros. Conclusion:Imatinib can be safely discontinued in pts with a CMR of at least 2 years duration. This category of pts might be cured from CML with tyrosine kinase inhibitors. Cure may not require the eradication of residual leukemic stem cells since it has been reported that the more sensitive PCR on DNA or RNA to assess CMR does not allow the prediction of relapse after discontinuation. In addition with this longer FU, positive fluctuation PCR results do not mean CML relapse or progression. It is thus conceivable that below a threshold of residual leukemic cells the inherent nature of the disease (illustrate by the Sokal score) and the duration of therapy are probably the most important factors to predict relapse after discontinuation. Disclosures:Mahon:Novartis Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria; Pfizzer: Honoraria.

Novel Proteasome Inhibitors to Overcome Bortezomib Resistance

The proteasome is an intracellular enzyme complex that degrades ubiquitin-tagged proteins and thereby regulates protein levels within the cell. Given this important role in maintaining cellular homeostasis, it is perhaps somewhat surprising that proteasome inhibitors have a therapeutic window. Proteasome inhibitors have demonstrated clinical efficacy in the treatment of multiple myeloma and mantle cell lymphoma and are under evaluation for the treatment of other malignancies. Bortezomib is the first and only Food and Drug Administration-approved proteasome inhibitor that inhibits this enzyme complex in a reversible fashion. Although bortezomib improves clinical outcomes when used as a single agent, most patients do not respond to this drug and those who do respond almost uniformly relapse. As such, efforts are underway to develop proteasome inhibitors that act through mechanisms distinct from that of bortezomib. Specifically, inhibitors that bind the active site of the proteasome and inhibit the complex irreversibly have been developed and are in advanced clinical trials. Inhibitors that act on sites of the proteasome outside of the catalytic center have also been identified and are in preclinical development. In this review, we discuss the structure and function of the proteasome. We then focus on the molecular biology, chemistry, and the preclinical and clinical efficacy of novel proteasome inhibitors as strategies to inhibit this target and overcome some forms of bortezomib resistance.

The War on Cancer: Progress at What Price?

The War on Cancer: Progress at What Price?

Mechanisms of mTOR inhibitor resistance in cancer therapy

Mammalian target of rapamycin (mTOR) is a conserved serine/threonine kinase that regulates cell cycle progression, protein translation, metabolism, and cellular proliferation. The mTOR pathway promotes cell proliferation under energy or nutrient-rich conditions by increasing ribosomal biogenesis and protein synthesis. Since enhanced activity of the mTOR pathway is frequently observed in malignant cells, inhibition of this kinase has become an attractive strategy to treat cancer. Rapamycin and its analogs temsirolimus, everolimus, and ridaforolimus referred to as "rapalogs" have demonstrated promising efficacy against renal cell carcinoma and are under investigation for the treatment of other malignancies. However, the emergence of drug resistance may ultimately limit the utility of rapalog therapy. Here we summarize the known mechanisms of resistance to mTOR-inhibitor therapy and describe potential strategies to overcome these for the current agents that target this pathway.

Inhibitors of mTOR

Inhibitors of mammalian target of rapamycin (mTOR) have been approved for the treatment of renal cell carcinoma and appear to have a role in the treatment of other malignancies. The primary objective of this drug review is to provide pharmacokinetic and dynamic properties of the commonly used drugs everolimus and temsirolimus. Additionally, information on clinical use, mechanism of action, bioanalysis, drug-drug interactions, alterations with disease or age, pharmacogenetics, and drug resistance is given. This overview should assist the treating medical oncologist in adjusting treatment with mTOR inhibitors to individual patient circumstances.

IDH Mutations Can Be Detected In 28.7% of All Normal Karyotype AML and Have Unfavourable Impact on the NPM1+/FLT3-ITD- Genotype

AbstractAbstract 102 Introduction:Mutations in IDH1 and IHD2 have recently been shown to play an important role in AML. As they code for enzymes from the citric acid cycle mutations within these genes from the mechanistical point of view are a totally new kind of mutation associated with AML. In IDH1 one mutational hot spot (amino acid R132) and in IDH2 two hotspots (R140 and R172) have been reported. We aimed at further delineating the impact of IDH1 and IDH2 mutations in AML and analyzed the interaction with other mutations in normal karyotype (NK) AML. Methods:526 AML patients were selected according to normal karyotype and availability of mutational status for FLT3-ITD, NPM1 and MLL-PTD. Further mutation analyses were available in subgroups of the cohort (FLT3-TKD: n=318, CEBPA: n=369, RUNX1: n=174, NRAS: n=220). Female/male ratio was 283/243 and age ranged from 20.0–90.1 years (median, 66.9 years). 435 had de novo AML (82.6%), 71 AML following MDS (s-AML,13.5%) and 20 AML after previous treatment of other malignancies (t-AML, 3.8%). The respective base exchanges in R132, R140, and R172 were analysed by a melting curve assay with subsequent sequencing of the positive samples. Results:Overall, in 151 pts (28.7%) IDH mutations (IDHmut) were detected. In detail, 68 mutations (12.9% of all cases) were detected in IDH1 (R131C: n=35, R131L: n=17, R131H: n=7, R131G: n=6, R131S: n=3) and 83 mutations (15.8%) in IDH2 (R140Q: n=72, R140L: n=2, R140W: n=1, N141G: n=1, R174K: n=7). IDH1mut and IDH2mut were mutually exclusive in this cohort. IDH1mut were more frequent in females (18.2% vs 8.6 % in males, p=0.001), whereas there was no sex difference for IDH2. According to history IDH1 was equally distributed in de novo AML, s-AML and t-AML whereas IDH2 was more frequent in de novo compared to s- and t-AML (19.6% vs. 7.6 vs 11.8%, p=0.048). According to FAB the most prevalent subtype was FAB M1 with IDHmut in 23.2% compared to 9.8% in all other FAB (in detail: IDH1: 44.8% vs. 23.9%, IDH2: 27.0% vs. 15.1%; p<0.001, for both). IDH1 was underrepresented in M4 (4.9% vs. 15.0 % in all other subtypes, p=0.004), whereas the distribution of IHD2 was not different in M4 vs. all others. The immunophenotype (n= 297) of IDHmut cases tended to be more immature and featured a lower expression of monocytic markers. The analyzed 78 IDHmut cases, as compared to 219 IDHwt cases, showed a significantly higher expression of MPO and CD117 while CD116, CD11b, CD14, CD15, CD36. CD56, CD64, CD65 and CD7 were lower expressed. Age, WBC count, and platelet count were not different between IDH1, IDH2 and IDHwt cases. IDH mutations are not mutually exclusive of other mutations. However, the frequency of CEBPAmut in IDHmut compared to IDHwt was decreased (7.7% vs. 13.7, p=0.001) (IDH1: 0% vs 11.7%, p=0.022 and IDH2: 7.7% vs 13.4%, p=0.053). MLL-PTD was more frequent in IDHmut vs. IDHwt (44.7 vs. 5.8%, p=0.039), however, this is restricted to IDH1mut vs. IDH1wt (26.3 vs. 6.3%, p=0.018). RUNX1mut are distributed equally in IDH2mut and IDH2wt (20.0% vs 27.3%) but are underrepresented in IDH1mut compared to IDH1wt (2.2% vs. 28.7%, p=0.068). FLT3-ITDs are equally distributed between IDHmut and IDHwt, however, those IDH1mut with FLT3-ITD have lower FLT3-ITD/FLT3wt ratios compared to FLT3-ITD+ IDH1wt cases (mean: 0.16 vs. 0.72; p=0.005). All other mutations were distributed equally in IDHmut compared to IDHwt. For survival analysis only cases with de novo AML <65 years were included (n=164, IDHmut: n=37, n=, IDHwt: 127). In the total analysis there was no effect on overall survival or event free survival (EFS). However there was a trend for shorter EFS of the IDHmut vs. IDHwt (median: 439 days vs. not reached, p=0.080) in cases with NPM1+/FLT3-ITD- genotype. For IDH2 there was a significant adverse effect in the NPM1+/FLT3-ITD- group (median EFS: 397 vs. 679 days, p=0.045). Summary:IDH mutations belong to the most frequent mutations in NK AML and can occur together with all other known mutations. There is a high preponderance for the FAB M1 subtype and a more immature immunophenotype for both IDH mutations and a strong female preponderance for IDH1. In addition, an adverse prognostic impact of IDH mutations was shown for the NPM1+/FLT3-ITD- genotype. Further analyses should focus on the definition of the role and place of IDH mutations for therapeutic decisions in patients with AML. Disclosures:Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial

Imatinib treatment significantly improves survival in patients with chronic myeloid leukaemia (CML), but little is known about whether treatment can safely be discontinued in the long term. We aimed to assess whether imatinib can be discontinued without occurrence of molecular relapse in patients in complete molecular remission (CMR) while on imatinib. In our prospective, multicentre, non-randomised Stop Imatinib (STIM) study, imatinib treatment (of >2 years duration) was discontinued in patients with CML who were aged 18 years and older and in CMR (>5-log reduction in BCR-ABL and ABL levels and undetectable transcripts on quantitative RT-PCR). Patients who had undergone immunomodulatory treatment (apart from interferon α), treatment for other malignancies, or allogeneic haemopoietic stem-cell transplantation were not included. Patients were enrolled at 19 participating institutions in France. In this interim analysis, rate of relapse was assessed by use of RT-PCR for patients with at least 12 months of follow-up. Imatinib was reintroduced in patients who had molecular relapse. This study is registered with ClinicalTrials.gov, number NCT00478985. 100 patients were enrolled between July 9, 2007, and Dec 17, 2009. Median follow-up was 17 months (range 1-30), and 69 patients had at least 12 months follow-up (median 24 months, range 13-30). 42 (61%) of these 69 patients relapsed (40 before 6 months, one patient at month 7, and one at month 19). At 12 months, the probability of persistent CMR for these 69 patients was 41% (95% CI 29-52). All patients who relapsed responded to reintroduction of imatinib: 16 of the 42 patients who relapsed showed decreases in their BCR-ABL levels, and 26 achieved CMR that was sustained after imatinib rechallenge. Imatinib can be safely discontinued in patients with a CMR of at least 2 years duration. Imatinib discontinuation in this setting yields promising results for molecular relapse-free survival, raising the possibility that, at least in some patients, CML might be cured with tyrosine kinase inhibitors.

Recent advances in bacillus Calmette–Guerin immunotherapy in bladder cancer

The concept of using Mycobacterium for cancer treatment goes back to the 19th Century. Today, bacillus Calmette-Guerin (BCG) vaccine is a well-established treatment for human bladder cancer that is arguably superior to intravesical chemotherapy for superficial disease and is commonly used as the first-line adjuvant treatment. Much has been learnt about the effects of BCG on bladder cancer and the immune system, but deeper understanding is required in order to improve its efficacy further, to be able to reliably predict responders and ultimately to adapt this most successful form of cancer immunotherapy for the treatment of other malignancies. This article summarizes the current understanding of BCG cancer immunotherapy mechanisms and discusses possible future developments.

Phase I study of vorinostat for patients with advanced solid tumors and hepatic dysfunction: An NCI Organ Dysfunction Working Group (ODWG) study (NCI #8057).

2545 Background: The histone deacetylase inhibitor, vorinostat, is FDA-approved for treating cutaneous T-cell lymphoma and is being evaluated for treatment of other malignancies. It is metabolized by glucuronidation and b-oxidation. We conducted a phase I study to determine the MTD and PK of vorinostat in patients (pts) with hepatic dysfunction (HD). Methods: Pts had solid malignancies, ECOG PS 0-2, normal bone marrow and renal function. HD was categorized as mild, moderate, or severe by NCI ODWG criteria. 16 pts with normal liver function were enrolled as controls. Initially all patients received a single oral dose of vorinostat (400 mg) followed by extensive PK sampling. After 1 week, vorinostat was given PO QD continuously until progression or toxicity. Vorinostat dose was escalated in sequential cohorts of pts within each HD category. Vorinostat concentrations in plasma were determined with a validated LC-MS/MS method and modeled noncompartmentally. Differences in PK were evaluated using a two-sided Kruskal-Wallis test. Results: 57 pts were enrolled (median age: 57 years, female: 24, PS 0/1: 86%). 41 pts had HD (mild: 15, moderate: 15, severe: 11).The majority of pts had GI malignancies (N=32). 8 of 9 pts who developed dose-limiting toxicity had grade 4 thrombocytopenia. There were no statistically significant differences in vorinostat PK parameters among the normal or HD categories. Disease stabilization was noted in 12 pts. Of 5 pts with adenoid cystic carcinoma, 1 had a PR and 4 had SD. A pt with papillary thyroid cancer has ongoing SD for > 2 years. Conclusions: The recommended doses of vorinostat for pts with mild, moderate, or severe HD are 300 mg, 200 mg, and 100 mg, respectively, on a daily continuous schedule. The PK of vorinostat were not altered by HD and do not explain the differences in recommended doses. Support: NO1 CM-62208 (SEP2C); UO1 CA-99168 (UOP); U01 CA-062505 (CCC); UO1 CA-062487 (Wayne State). HD Cmax(μ M) tmax(h) t1/2(h) AUCINF(μ M*h) ClAPP(l/min) Mean (SD) Normal 1.4 (0.5) 1.4 (0.8) 2.5 (1.2) 5.1 (1.9) 6.4 (5.1) Mild 2.2 (1.1) 2.3 (2.0) 2.0 (1.4) 7.7 (3.4) 4.0 (1.8) Moderate 1.7 (0.6) 2.7 (1.9) 3.5 (2.8) 7.5 (2.4) 3.8 (1.6) Severe 1.8 (0.7) 2.6 (2.2) 2.9 (1.5) 8.3 (5.1) 4.2 (2.3) Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck

Coencapsulation of Arsenic‐ and Platinum‐based Drugs for Targeted Cancer Treatment

Arsenic- and platinum-based drugs are highly potent but also toxic agents used in cancer therapy.[1, 2] Arsenic trioxide (Trisenox®, As2O3) is a front-line drug for treatment of acute promyelocytic leukemia[3] and is in clinical trials for treatment of other malignancies, including multiple myeloma.[4] However, clinical outcomes of As2O3 in solid tumors have been poor in many cases,[1, 5] mainly due to limited bioavailability of the drug in the tumor site. Clinical application to solid tumors is also impeded by toxicity including neutropenia, liver failure and cardiac toxicity[1, 6] at higher doses.[7] Cisplatin (cis-diamine dichloroplatinumII, cisPt, Figure 1a) is commonly used in the treatment of a variety of solid tumors, including lung, ovarian, bladder, and testicular cancer.[2] The active intracellular species appear to be the hydrolyzed monoaqua- and diaqua-cisplatin (aqua-cisPt, Figure 1a).[8] Broader therapeutic applications of cisPt are limited by serious systemic toxicities, development of drug resistance, and rapid inactivation of the drug due to complexation with plasma and tissue proteins.[2, 8] These problems can be reduced by using a drug delivery system that prevents drug deactivation, extends the circulation time of drug in blood and increases its accumulation at tumor sites.[9] Lipid-based carriers have been successfully applied in clinics for improving the therapeutic efficacy of numerous drugs, such as liposomal doxorubicin (Doxil®),[10] mainly via the enhanced permeability and retention (EPR) effects.[9]

Folate-mediated intracellular drug delivery increases the anticancer efficacy of nanoparticulate formulation of arsenic trioxide

Arsenic trioxide (As(2)O(3)) is a frontline drug for treatment of acute promyelocytic leukemia and is in clinical trials for treatment of other malignancies, including multiple myeloma; however, efforts to expand clinical utility to solid tumors have been limited by toxicity. Nanoparticulate forms of As(2)O(3) encapsulated in 100-nm-scale, folate-targeted liposomes have been developed to lower systematic toxicity and provide a platform for targeting this agent. The resultant arsenic "nanobins" are stable under physiologic conditions but undergo triggered drug release when the pH is lowered to endosomal/lysosomal levels. Cellular uptake and antitumor efficacy of these arsenic liposomes have been evaluated in folate receptor (FR)-positive human nasopharyngeal (KB) and cervix (HeLa) cells, as well as FR-negative human breast (MCF-7) tumor cells through confocal microscopy, inductively coupled plasma mass spectroscopy, and cytotoxicity studies. Uptake of folate-targeted liposomal arsenic by KB cells was three to six times higher than that of free As(2)O(3) or nontargeted liposomal arsenic; the enhanced uptake occurs through folate-mediated endocytosis, leading to a 28-fold increase in cytotoxicity. In contrast, tumor cells with lower FR density on the surface (HeLa and MCF-7) showed much less uptake of the folate-targeted drug and lower efficacy. In cocultures of KB and MCF-7 cells, the folate-targeted arsenic liposomes were exclusively internalized by KB cells, showing high targeting specificity. Our studies further indicate that folate-targeted delivery of As(2)O(3) with coencapsulated nickel(II) ions (as a nontoxic adjuvant) potentiates the As(2)O(3) efficacy in relatively insensitive solid tumor-derived cells and holds the promise of improving drug therapeutic index.

Janus Kinase Mutations

The chronic myeloproliferative neoplasms (MPNs) polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (MF) are commonly associated with mutations in the Janus kinase gene JAK2. A hallmark of PV is an abundance of red blood cells; ET, too many platelets; and MF, accumulation of neutrophils and monocytes accompanied by bone marrow fibrosis and bone marrow failure. Although knowledge of PV, ET, and MF has expanded considerably in the last decade, the pathophysiology behind these disorders is complex, and some of the underlying mechanisms are still unknown. The knowledge gap for these diseases has been compounded by the observation that a subset of patients with PV, ET, and MF do not present with mutations that activate JAK2. Recent studies suggest JAK inhibitors may offer significant benefit to patients with these MPNs and may have a role in the treatment of other malignancies that are also driven, at least in part, by activation of JAK signaling. However, additional genetic and functional studies are needed to identify the patients that will benefit most from JAK kinase inhibitors.

Acute Erythroleukemia: An Analysis of 108 Patients Treated with Cytarabine-Containing Regimens at the M.D. Anderson Cancer Center.

Acute erythrocytic leukemia (AML-M6) is an uncommon subtype of acute myeloid leukemia (AML). It usually presents as a proliferation of dysplastic erythroid elements mixed with blasts of myeloid origin, although there are some rare cases of pure erythroid proliferation (DiGuglielmo's disease). It has previously been associated with a poor prognosis. Here, we report the experience at the M.D. Anderson Cancer Center. From January, 1980 to May, 2006 there were 2992 patients with newly diagnosed AML (excluding APL), and 108 (4%) had the diagnosis of AML-M6. Diagnosis was based on morphological features according to the FAB classification, PAS-positivity by cytochemistry and immunophenotypical positivity for glycophorin A when available. Seventy (65%) were males; median age was 60 years (range 17 – 85). Antecedent hematological disorder (AHD) and/or MDS was present in 54 patients (50%) compared to 40% in other AML patients (p=0.056), and 27 (25%) patients had previously received treatment for other malignancies. The median white blood cell count at diagnosis was 2.5x109/L (0.3–45.1), hemoglobin 7.8 g/dL (2.5–12.6) and platelet count 40x109/L (3–22). Information about bone marrow dysplasia was available in 80 patients. Significant morphological dysplasia of erythroid lineage was found in 66 (83%), of myeloid lineage in 38 (48%) and of megakaryocytic lineage in 36 (45%) cases. Cytogenetic analysis was available in 106 (98%) cases, and was abnormal in 77 (71%) patients. The most common abnormalities were: Monosomy 5/Monosomy 7 in 50 (46.3%) and Trisomy 8 in 9 (8.3%). Poor risk cytogenetics were found in 46% of patients with AML-M6, comparing to 19% of the control group (other AML patients excluding APL) (p<0.001). All patients received induction chemotherapy containing cytarabine. Complete remission rates were 63% for AML-M6 patients, comparing to 58% for the control group (p = 0.285). Seventeen patients (15.7%) were refractory and 23 (21.3%) had induction death. Median disease free survival of AML-M6 patients was 31 weeks, compared to 49 weeks for the control group (p = 0.03). Median overall survival of AML-M6 patients was 33 weeks, compared to 42 weeks for the control group (p = 0.190). A total of 24 patients underwent allogeneic stem cell transplantation. Their median survival after transplantation was 32 weeks. We conclude that acute erythrocytic leukemia is a rare subtype of AML. It is commonly associated with a previous diagnosis of MDS and often presents with dysplastic features at diagnosis. It is frequently associated with poor-risk cytogenetics and a poor outcome.