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1.  Cytogenetic Prioritization with Inclusion of Molecular Markers Predicts Outcome in Previously Untreated Chronic Lymphocytic Leukemia Patients Treated with Fludarabine or Fludarabine Plus Cyclophosphamide: A Long-Term Follow-Up Study of the U.S. Intergroup Phase III Trial E2997 
Leukemia & lymphoma  2015;56(11):3031-3037.
Fludarabine (F) and cyclophosphamide (C) remain backbones of up-front chemotherapy regimens for chronic lymphocytic leukemia (CLL). We report long-term follow-up of a randomized F versus FC trial in untreated, symptomatic CLL (NCT00003764, clinicaltrials.gov). With median follow-up of 88 months, estimated median progression-free survival (PFS) was 19.3 versus 48.1 months for F (N=109) and FC (N=118) respectively (p<0.0001), while median overall survival (OS) was 88.0 versus 79.1 months respectively (p=0.96). In multivariable analyses, variables associated with inferior PFS and OS respectively were older age (p=0.002, p<0.001), Rai stage ≥II (p=0.006, p=0.02) and sex (p=0.03, PFS only). Occurrence of del(17)(p13.1) predicted shorter PFS and OS (p<0.0001 for each), as did del(11q)(22.3) (p<0.0001 and p=0.005, respectively), trisomy 12 with mutated Notch1 (p=0.003 and p=0.03, respectively) and unmutated IGHV (p=0.009 and p=0.002, respectively), all relative to patients without these features. These data confirm results from shorter follow-up and further justify targeted therapies for CLL.
doi:10.3109/10428194.2015.1023800
PMCID: PMC4688910  PMID: 25721902
fludarabine; cyclophosphamide; chemotherapy; chronic lymphocytic leukemia
2.  A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy 
Annals of hematology  2016;95(7):1137-1143.
Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m2 followed by a 4-h infusion of 30 mg/ m2 once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.
Registration number at ClinicalTrials.gov: NCT00377104.
doi:10.1007/s00277-016-2683-1
PMCID: PMC4981588  PMID: 27118540
Flavopiridol; Chronic lymphocytic leukemia
3.  Jumping translocations, a novel finding in chronic lymphocytic leukaemia 
British journal of haematology  2015;170(2):200-207.
Summary
A jumping translocation (JT) is a rare cytogenetic aberration that can occur in haematological malignancy. It involves the translocation of the same fragment of donor chromosome onto two or more recipient chromosomes, typically in different cells. In this study, we describe the first series of chronic lymphocytic leukaemia (CLL) patients with JTs reported to date. Following a review of 878 CLL patient karyotypes, we identified 26 patients (3%) with 97 JTs. The most commonly occurring breakpoint in these translocations was 17p11.2. Loss of TP53 was identified prior to or at the same time as JT in 23 of 26 patients (88%). All patients eventually developed a complex karyotype. All but one patient has required treatment for CLL, with estimated median time to treatment of 11.5 months. This study establishes JTs as a recurrent abnormality found in CLL patients with aggressive disease. JTs contribute to complex karyotypes and, in many cases, are involved in chromosomal rearrangements that result in loss of the tumour suppressor gene TP53.
doi:10.1111/bjh.13422
PMCID: PMC4490025  PMID: 25891862
chronic lymphocytic leukaemia; chromosomal rearrangement; cancer cytogenetics; complex karyotype; TP53
4.  Final Results of EFC6663: A Multicenter, International, Phase 2 Study of Alvocidib for Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia 
Leukemia research  2015;39(5):495-500.
Purpose
Chronic lymphocytic leukemia (CLL) patients refractory to fludarabine based therapies have poor outcomes with currently available therapies. Early phase studies of alvocidib showed activity in relapsed CLL including patients with high risk genomic features and those refractory to fludarabine. A multi-center, international, phase II study of alvocidib in fludarabine refractory CLL was undertaken to validate these early results.
Patients and Methods
Patients with fludarabine refractory CLL or prolymphocytic leukemia arising from CLL were treated with single agent alvocidib. The primary outcome measure was overall response rate, with secondary outcomes including survival, toxicity, and response duration.
Results
One hundred and sixty five patients were enrolled at 34 centers, and 159 patients were treated. The median age was 61 years, the median number of prior therapies was 4, and 96% of patients were fludarabine refractory. The investigator-assessed overall response rate was 25%; the majority of responses were partial. Response rates were lower among patients with del(17p) (14%), but equivalent in patients with del(11q) or bulky lymphadenopathy. Median progression free and overall survival were 7.6 and 14.6 months respectively. Tumor lysis occurred in 39 patients (25%), and 13 received hemodialysis. Diarrhea, fatigue, and hematologic toxicities were common.
Conclusion
Alvocidib has clinical activity in patients with advanced, fludarabine refractory CLL. Clinical responses were observed in patients with high risk clinical and genomic features. With careful monitoring, alvocidib has a manageable safety profile. Future studies should focus on discovery of biomarkers of clinical response and tumor lysis, and enhanced supportive care measures.
doi:10.1016/j.leukres.2015.02.001
PMCID: PMC4557608  PMID: 25804339
5.  Targeting Mutant BRAF with Vemurafenib in Relapsed or Refractory Hairy Cell Leukemia 
The New England journal of medicine  2015;373(18):1733-1747.
BACKGROUND
BRAF-V600E is the genetic lesion underlying hairy cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy cell leukemia who relapsed after or were refractory to purine analogues.
METHODS
We conducted in Italy and USA two phase-2 single-arm multicenter studies of vemurafenib (960 mg twice daily) given for a median of 16 and 18 weeks, respectively. Primary endpoints were complete remission rate and overall response rate. Patient enrollment was completed (n=28) in the Italian trial in April 2013 and is still open (n=26/36) in the American trial.
RESULTS
Drug-related adverse events were usually of grade 1-2, and those most frequently requiring dose reductions were rash and arthralgia/arthritis; secondary cutaneous tumors (treated with simple excision) developed in 6/50 patients. Overall response rates were 96% (25/26 evaluable Italian patients) and 100% (24/24 evaluable American patients), obtained after a median of 8 weeks and 12 weeks, respectively. Complete response rates were 34.6% (9/26) and 41.7% (10/24), respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free and treatment-free survivals were respectively 19 and 25 months in complete responders, and 6 and 18 months in partial responders. In the American trial, 1-year progression-free and overall survival were 73% and 91%, respectively. Frequent persistence of phospho-ERK+ bone marrow leukemic cells at the end of treatment suggests bypass MEK-ERK reactivation as a resistance mechanism.
CONCLUSIONS
A short oral course of vemurafenib proved safe and highly effective in relapsed/refractory hairy cell leukemia patients (Funded by AIRC, ERC, Roche/Genentech and others; EudractCT number: 2011-005487-13, ClinicalTrials.gov number NCT01711632).
doi:10.1056/NEJMoa1506583
PMCID: PMC4811324  PMID: 26352686
hairy cell leukemia; BRAF mutations; BRAF inhibitors; vemurafenib
6.  Etiology of Ibrutinib Discontinuation and Outcomes in Chronic Lymphocytic Leukemia Patients 
JAMA oncology  2015;1(1):80-87.
Importance
The Bruton’s Tyrosine Kinase inhibitor ibrutinib is effective in patients with chronic lymphocytic leukemia (CLL). Reasons for discontinuation from this drug and outcomes following discontinuation have not been evaluated outside of clinical trials with relatively short follow-up.
Objective
To determine features associated with discontinuation of ibrutinib and outcomes.
Design
308 patients participating in four sequential trials of ibrutinib were included. These trials accrued patients included in this analysis from May 2010 until April 2014, and data were locked in June 2014.
Setting
The Ohio State University Comprehensive Cancer Center
Participants
Patients with CLL enrolled on 4 sequential clinical trials.
Main Outcome Measure
Patients were evaluated for time to discontinuation, reasons for discontinuation, and survival following discontinuation. For patients who discontinued due to progression, targeted deep sequencing was performed in samples at baseline and relapse.
Results
With a median follow-up of 20 months, 232 patients remain on therapy, 31 have discontinued because of progression, and 45 have discontinued for other reasons. Disease progression includes Richter’s transformation or progressive CLL. Richter’s appeared to occur early and CLL progressions later (cumulative incidence at 12 months: 4.5% (95% CI: 2.0% to 7.0%) and 0.3% (95% CI: 0% to 1.0%), respectively). Median survival following Richter’s transformation was 3.5 months (95% CI: 0.3–6.0), and 17.6 months (95% CI: 4.7-not reached) following CLL progression. Sequencing on peripheral blood from 8 patients with Richter’s transformation revealed 2 with mutations in BTK, and a lymph node sample showed no mutations in BTK or PLCγ2. Deep sequencing on 11 patients with CLL progression revealed BTK or PLCγ2 mutations in all. These mutations were not identified pre-treatment in any patient.
Conclusions and Relevance
This single institution experience with ibrutinib confirms it to be an effective therapy and identifies, for the first time, baseline factors associated with ibrutinib discontinuation. Outcomes data show poor prognosis after discontinuation, especially for those patients with Richter’s transformation. Finally, sequencing data confirm initial reports associating mutations in BTK and PLCγ2 with progression and clearly show that CLL progressions are associated with these mutations, while Richter’s transformation is likely not.
doi:10.1001/jamaoncol.2014.218
PMCID: PMC4520535  PMID: 26182309
7.  Reduced Occurrence of Tumor Flare with Flavopiridol Followed by Combined Flavopiridol and Lenalidomidein Patients with Relapsed Chronic Lymphocytic Leukemia (CLL) 
American journal of hematology  2015;90(4):327-333.
Flavopiridol and lenalidomide have activity in refractory CLL without immunosuppression or opportunistic infections seen with other therapies. We hypothesized that flavopiridol treatment could adequately de-bulk disease prior to lenalidomide therapy, decreasing the incidence of tumor flare with higher doses of lenalidomide. In this Phase I study, the maximum tolerated dose was not reached with treatment consisting of flavopiridol 30 mg/m2 intravenous bolus (IVB) + 30 mg/m2 continuous intravenous infusion (CIVI) cycle (C) 1 day (D) 1 and 30 mg/m2 IVB + 50 mg/m2 CIVI C1 D8,15 and C2-8 D3,10,17 with lenalidomide 15 mg orally daily C2-8 D1-21. There was no unexpected toxicity seen, including no increased tumor lysis, tumor flare (even at higher doses of lenalidomide) or opportunistic infection. Significant clinical activity was demonstrated, with a 51% response rate in this group of heavily pretreated patients. Biomarker testing confirmed association of mitochondrial priming of the BH3 only peptide Puma with response.
doi:10.1002/ajh.23946
PMCID: PMC4552311  PMID: 25639448
chronic lymphocytic leukemia; flavopiridol; lenalidomide; tumor flare; tumor lysis mitochondrial profiling
8.  Dinaciclib is a Novel Cyclin Dependent Kinase Inhibitor with Significant Clinical Activity in Relapsed and Refractory Chronic Lymphocytic Leukemia 
Leukemia  2015;29(7):1524-1529.
Dinaciclib (SCH727965) is a selective CDKi chosen for clinical development based upon a favorable therapeutic index in cancer xenograft models. We performed a phase I dose escalation study of dinaciclib in relapsed and refractory CLL patients with intact organ function and WBC < 200 × 109/L. Five separate dose levels (5 mg/m2, 7 mg/m2, 10 mg/m2, 14 mg/m2, and 17 mg/m2) were explored dosing on a weekly schedule × 3 with one week off (4 week cycles) using a standard 3+3 design with expansion cohorts to optimize safety. Fifty two patients were enrolled with relapsed and refractory CLL. Escalation through cohorts occurred with two DLTs at the 17 mg/m2 dose (TLS and pneumonia). The phase II expansion occurred at 14 mg/m2 with sixteen patients receiving this dose with one DLT (TLS). Additional stepped up dosing to the MTD was examined in 19 patients at this dose. Adverse events included cytopenias, transient laboratory abnormalities, and tumor lysis syndrome. Responses occurred in 28 (54%) of patients independent of del(17)(p13.1) with a median progression free survival of 481 days. Dinaciclib is clinically active in relapsed CLL including those patients with high risk del(17)(p13.1) disease and warrants future study.
doi:10.1038/leu.2015.31
PMCID: PMC4551390  PMID: 25708835
Dinaciclib; CDK inhibitor; tumor lysis syndrome; chronic lymphocytic leukemia
9.  A Phase 1 Trial of Single Agent Reolysin in Patients with Relapsed Multiple Myeloma 
Introduction
Reolysin®, a proprietary isolate of reovirus Type 3 Dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase 1 – 2 trials; no clinical trials have been conducted in patients with hematologic malignancies.
Methodologies
A phase 1 trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by In situ based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer up regulated gene 2 (CUG2) were evaluated in patient samples and MM cell lines. Neutralizing Anti-Reovirus Antibody (NARA) assay was performed weekly during cycle 1.
Results
There were no dose limiting toxicities (DLTs), patients reached the 3 x 1010 TCID50 daily on days 1-5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. In situ hybridization demonstrated reoviral genome confined in MM cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA positive cells. The longest durations of stable disease were 4, 5 and 8 months.
Conclusions
Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within MM cells. Our data support that in MM cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers.
doi:10.1158/1078-0432.CCR-14-1404
PMCID: PMC4253985  PMID: 25294913
Reolysin; Reovirus; Multiple myeloma
10.  Sorbicillinoid Analogues with Cytotoxic and Selective Anti-Aspergillus Activities from Scytalidium album 
The Journal of antibiotics  2014;68(3):191-196.
As part of an ongoing project to explore filamentous fungi for anticancer and antibiotic leads, eleven compounds were isolated and identified from an organic extract of the fungus Scytalidium album (MSX51631) using bioactivity-directed fractionation against human cancer cell lines. Of these, eight were a series of sorbicillinoid analogues (1–8), of which four were new [scalbucillin A (2), scalbucillin B (3), scalbucillin C (6), and scalbucillin D (8)], two were phthalides (9–10), and one was naphthalenone (11). Compounds (1–11) were tested in the MDA-MB-435 (melanoma) and SW-620 (colon) cancer cell lines. Compound 1 was the most potent with IC50 values of 1.5 and 0.5 μM, respectively, followed by compound 5, with IC50 values of 2.3 and 2.5 μM at 72 h. Compound 1 showed a 48-h IC50 value of 3.1 μM when tested against the lymphocytic leukemia cell line OSU-CLL, while the nearly identical compound 5 had almost no activity in this assay. Compounds 1 and 5 showed selective and equipotent activity against Aspergillus niger with minimum inhibitory concentration values of 0.05 and 0.04 μg/ml (0.20 and 0.16 μM), respectively. The in vitro hemolytic activity against sheep erythrocytes of compounds 1 and 5 was investigated and were found to provoke 10% hemolysis at 52.5 and 45.0 μg/ml, respectively, indicative of a promising safety factor.
doi:10.1038/ja.2014.125
PMCID: PMC4372511  PMID: 25248727
cytotoxicity; fungus; antifungal; hemolysis; Scytalidium; sorbicillinoid analogues
12.  Flavaglines target primitive leukemia cells and enhance anti-leukemia drug activity 
Leukemia  2014;28(10):1960-1968.
Identification of agents that target human leukemia stem cells (LSCs) is an important consideration for the development of new therapies. The present study demonstrates that rocaglamide and silvestrol, closely related natural products from the flavagline class of compounds, are able to preferentially kill functionally defined LSCs while sparing normal stem and progenitor cells. In addition to efficacy as single agents, flavaglines sensitize leukemia cells to several anti-cancer compounds, including front-line chemotherapeutic drugs used to treat leukemia patients. Mechanistic studies indicate that flavaglines strongly inhibit protein synthesis, leading to the reduction of short-lived anti-apoptotic proteins. Notably though, treatment with flavaglines alone or in combination with other drugs, yields a much stronger cytotoxic activity towards leukemia cells than the translational inhibitor temsirolimus. These results indicate that the underlying cell death mechanism of flavaglines is more complex than simply inhibiting general protein translation. Global gene expression profiling and cell biological assays identified Myc inhibition and the disruption of mitochondrial integrity to be features of flavaglines, which we propose contribute to their efficacy in targeting leukemia cells. Together, these findings indicate that rocaglamide and silvestrol are distinct from clinically available translational inhibitors and represent promising candidates for the treatment of leukemia.
doi:10.1038/leu.2014.93
PMCID: PMC4148474  PMID: 24577530
leukemia; stem cells; silvestrol; rocaglamide; flavaglines
13.  Up-regulation of CDK9 kinase activity and Mcl-1 stability contributes to the acquired resistance to cyclin-dependent kinase inhibitors in leukemia 
Oncotarget  2014;6(5):2667-2679.
Flavopiridol is a small molecule inhibitor of cyclin-dependent kinases (CDK) known to impair global transcription via inactivation of positive transcription elongation factor b. It has been demonstrated to have significant activity predominantly in chronic lymphocytic leukemia and acute myeloid leukemia in phase I/II clinical trials while other similar CDK inhibitors are vigorously being pursued in pre-clinical and clinical studies. Although flavopiridol is a potent therapeutic agent against blood diseases, some patients still have primary or acquired resistance throughout their clinical course. Considering the limited knowledge of resistance mechanisms of flavopiridol, we investigated the potential mechanisms of resistance to flavopiridol in a cell line system, which gradually acquired resistance to flavopiridol in vitro, and then confirmed the mechanism in patient samples. Herein, we present that this resistant cell line developed resistance through up-regulation of phosphorylation of RNA polymerase II C-terminal domain, activation of CDK9 kinase activity, and prolonged Mcl-1 stability to counter flavopiridol's drug actions. Further analyses suggest MAPK/ERK activation-mediated Mcl-1 stabilization contributes to the resistance and knockdown of Mcl-1 in part restores sensitivity to flavopiridol-induced cytotoxicity. Altogether, these findings demonstrate that CDK9 is the most relevant target of flavopiridol and provide avenues to improve the therapeutic strategies in blood malignancies.
PMCID: PMC4413609  PMID: 25596730
Flavopiridol; Mcl-1; cyclin-dependent kinase 9 (CDK9); cyclin-dependent kinase (CDK) inhibitor; and leukemia
14.  The translation inhibitor silvestrol exhibits direct anti-tumor activity while preserving innate and adaptive immunity against EBV-driven lymphoproliferative disease 
Oncotarget  2014;6(5):2693-2708.
Treatment options for patients with Epstein-Barr Virus-driven lymphoproliferative diseases (EBV-LPD) are limited. Chemo-immunotherapeutic approaches often lead to immune suppression, risk of lethal infection and EBV reactivation, thus it is essential to identify agents that can deliver direct anti-tumor activity while preserving innate and adaptive host immune surveillance. Silvestrol possesses direct anti-tumor activity in multiple hematologic malignancies while causing minimal toxicity to normal mononuclear cells. However, the effects of silvestrol on immune function have not been described. We utilized in vitro and in vivo models of EBV-LPD to simultaneously examine the impact of silvestrol on both tumor and normal immune function. We show that silvestrol induces direct anti-tumor activity against EBV-transformed lymphoblastoid cell lines (LCL), with growth inhibition, decreased expression of the EBV oncogene latent membrane protein-1, and inhibition of the downstream AKT, STAT1 and STAT3 signaling pathways. Silvestrol promoted potent indirect anti-tumor effects by preserving expansion of innate and EBV antigen-specific adaptive immune effector subsets capable of effective clearance of LCL tumor targets in autologous co-cultures. In an animal model of spontaneous EBV-LPD, silvestrol demonstrated significant therapeutic activity dependent on the presence of CD8-positive T-cells. These findings establish a novel immune-sparing activity of silvestrol, justifying further exploration in patients with EBV-positive malignancies.
PMCID: PMC4413611  PMID: 25393910
Lymphoproliferative disease; EBV; silvestrol; immunomodulation
15.  Phase I study of GTI-2040, a ribonucleotide reductase antisense, with high dose cytarabine in patients with relapsed/refractory acute myeloid leukemia 
Leukemia & lymphoma  2013;55(6):1332-1336.
We hypothesized that GTI-2040, a 20-mer oligonucleotide complementary to the R2 subunit mRNA of ribonucleotide reductase, combined with high dose cytarabine (HiDAC) would result in enhanced cytotoxicity by favoring Ara-CTP DNA incorporation. In a phase I dose escalation trial, adults (≥60 years) with refractory or relapsed acute myeloid leukemia (AML) received daily HiDAC plus infusional GTI-2040. Using a novel assay, evidence of intracellular drug accumulation and target R2 down-regulation was observed. GTI-2040/HiDAC can be administered safely. However, with no complete remissions observed, alternative doses and schedules may need to be investigated to achieve clinical activity in older patients with AML.
doi:10.3109/10428194.2013.838764
PMCID: PMC4298748  PMID: 24015841
Acute myeloid leukemia; antisense therapy; phase I study; GTI-2040; ribonucleotide reductase
18.  Flavopiridol Can Be Safely Administered Using a Pharmacologically Derived Schedule and Demonstrates Activity in Relapsed and Refractory Non-Hodgkin’s Lymphoma 
American journal of hematology  2013;89(1):19-24.
Flavopiridol is a broad cyclin-dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) for single-agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non-Hodgkin’s lymphoma. Dose was escalated independently in one of four cohorts: indolent B-cell (cohort 1), mantle cell (cohort 2), intermediate grade B-cell including transformed lymphoma (cohort 3), and T-/NK-cell excluding primary cutaneous disease (cohort 4). Forty-six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common non-hematologic toxicties included diarrhea and fatigue. Biochemical tumor lysis was observed in only 2 patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B-cell). Dose-limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m2 bolus + 50 mg/m2 continuous infusion weekly for 4 consecutive weeks of a 6 week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (2 mantle cell, 3 indolent B-cell, and 1 diffuse large B-cell). The single-agent activity of this first-generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination.
doi:10.1002/ajh.23568
PMCID: PMC4150545  PMID: 23959599
flavopiridol; non-Hodgkin’s lymphoma; cyclin-dependent kinase inhibitors; phase 1 trial; pharmacokinetics
19.  Standard Pentostatin Dose Reductions in Renal Insufficiency are not Adequate: Selected Patients with Steroid-Refractory Acute Graft-versus-Host Disease 
Clinical pharmacokinetics  2013;52(8):705-712.
Background and Objective
Pentostatin is an irreversible inhibitor of adenosine deaminase and has been used to prevent graft-versus-host disease (GVHD) and to treat both acute and chronic GVHD. Dose reduction equations for patients with renal insufficiency are based on few patients with limited pharmacokinetic and clinical results. This phase II study (NCT00201786) was conducted to assess pentostatin efficacy and infectious complications seen from our previous phase I study in steroid-refractory acute GVHD (aGVHD).
Patients and Methods
Hospitalized patients with steroid-refractory aGVHD were given pentostatin 1.5 mg/m2/day intravenously on days 1–3 of each 14 day cycle. Prior to each dose, dose modifications were based on Cockcroft-Gault estimated creatinine clearance (eCrCL) with 30–50 ml/min/1.73m2 leading to a 50% dose reduction and eCrCL< 30 ml/min/1.73m2 leading to study removal. Plasma pentostatin area under the concentration-time curve (AUC) and incidence of infectious complications were evaluated.
Results
Two of the eight patients treated demonstrated excessive pentostatin exposure as determined by measurement of AUC. One of these patients had renal impairment while the other patient demonstrated borderline renal function. Despite dose reduction to 0.75 mg/m2, AUCs were significantly increased compared to the other patients in this study. Seven of eight patients treated with pentostatin had cytomegalovirus (CMV) viremia after pentostatin treatment; however none developed proven CMV disease.
Conclusion
A 50% dose reduction in patients with eCrCL 30–50 ml/min/1.73m2 seems reasonable. However, the eCrCL should be interpreted with extreme cautions in patients who are critically ill and/or with poor performance status. Renal function assessment based on the Cockcroft-Gault method could be significantly overestimated thus risking pentostatin over-dosing. These results imply a need to closely monitor pentostatin exposure in patients with renal insufficiency.
doi:10.1007/s40262-013-0064-7
PMCID: PMC3720841  PMID: 23588536
20.  A phase I study of prolonged infusion of triapine in combination with fixed dose rate gemcitabine in patients with advanced solid tumors 
Investigational new drugs  2012;31(3):685-695.
Summary
Purpose
Prolonged exposure of cancer cells to triapine, an inhibitor of ribonucleotide reductase, followed by gemcitabine enhances gemcitabine activity in vitro. Fixed-dose-rate gemcitabine (FDR-G) has improved efficacy compared to standard-dose. We conducted a phase I trial to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of prolonged triapine infusion followed by FDR-G.
Experimental Design
Triapine was given as a 24-hour infusion, immediately followed by FDR-G (1000 mg/m2 over 100-minute). Initially, this combination was administered days 1 and 8 of a 21-day cycle (Arm A, triapine starting dose 120 mg); but because of myelosuppression, it was changed to days 1 and 15 of a 28-day cycle (Arm B, starting dose of triapine 75 mg). Triapine steady-state concentrations (Css) and circulating ribonucleotide reductase M2-subunit (RRM2) were measured.
Results
Thirty-six patients were enrolled. The MTD was determined to be triapine 90 mg (24-hour infusion) immediately followed by gemcitabine 1000 mg/m2 (100-minute infusion), every 2 weeks of a 4-week cycle. DLTs included grade 4 thrombocytopenia, leukopenia and neutropenia. The treatment was well tolerated with fatigue, nausea/vomiting, fever, transaminitis, and cytopenias being the most common toxicities. Among 30 evaluable patients, 1 had a partial response and 15 had stable disease. Triapine PK was similar, although more variable, compared to previous studies using doses normalized to body-surface-area. Steady decline in circulating levels of RRM2 may correlate with outcome.
Conclusions
This combination was well tolerated and showed evidence of preliminary activity in this heavily pretreated patient population, including prior gemcitabine failure.
doi:10.1007/s10637-012-9863-1
PMCID: PMC3646991  PMID: 22847785
Triapine; Gemcitabine; Phase I; Clinical Trial
21.  Phase I study of azacitidine and bortezomib in adults with relapsed or refractory acute myeloid leukemia 
Leukemia & lymphoma  2013;55(6):1304-1308.
We previously reported that bortezomib indirectly modulates transcription of DNA methyltransferase 1 (DNMT). We designed a phase I study of azacitidine (a direct DNMT inhibitor) plus bortezomib in acute myeloid leukemia (AML) to determine safety and tolerability. Twenty-three adults with relapsed/refractory AML received azacitidine 75mg/m2 daily on days 1-7. Bortezomib was dose escalated from 0.7mg/m2 on days 2 and 5 to 1.3mg/m2 on days 2, 5, 9, and 12. The target dose was reached without dose limiting toxicities. Infection and/or febrile neutropenia were frequent. Patients received a median of 2 cycles of therapy (range, 1-12+). Five of 23 patients achieved remission including two with morphologic and cytogenetic complete response (CR) and three with CR and incomplete count recovery (CRi). Of CR/CRi responders with cytogenetic abnormalities at baseline, three of four achieved cytogenetic CR. The combination of azacitidine and bortezomib was tolerable and active in this cohort of poor-risk previously-treated AML patients.
doi:10.3109/10428194.2013.833333
PMCID: PMC3925754  PMID: 23952243
Relapsed AML; bortezomib; velcade
22.  A Pharmacokinetic/Pharmacodynamic Model of Tumor Lysis Syndrome in Chronic Lymphocytic Leukemia Patients Treated with Flavopiridol 
Purpose
Flavopiridol, the first clinically evaluated cyclin dependent kinase inhibitor, demonstrates activity in patients with refractory chronic lymphocytic leukemia, but prevalent and unpredictable tumor lysis syndrome (TLS) presents a major barrier to its broad clinical use. The purpose of this study was to investigate the relationships between pretreatment risk factors, drug pharmacokinetics, and TLS.
Experimental Design
A population pharmacokinetic/pharmacodynamic model linking drug exposure and TLS was developed. Plasma data of flavopiridol and its glucuronide metabolite (flavo-G) were obtained from 111 patients treated in early phase trials with frequent sampling following initial and/or escalated doses. TLS grading was modeled with logistic regression as a pharmacodynamic endpoint. Demographics, baseline disease status, and blood chemistry variables were evaluated as covariates.
Results
Gender was the most significant pharmacokinetic covariate, with females displaying higher flavo-G exposure than males. Glucuronide metabolite exposure was predictive of TLS occurrence, and bulky lymphadenopathy was identified as a significant covariate on TLS probability. The estimated probability of TLS occurrence in patients with baseline bulky lymphadenopathy < 10 cm or > 10 cm during the first two treatments was 0.111 (SE% 13.0%) and 0.265, (SE% 17.9%) respectively, when flavo-G area under the plasma concentration vs. time curve was at its median value in whole patient group.
Conclusions
This is the first population pharmacokinetic/pharmacodynamic model of TLS. Further work is needed to explore potential mechanisms and to determine if the associations between TLS, gender and glucuronide metabolites are relevant in CLL patients treated with other cyclin dependent kinase inhibitors.
doi:10.1158/1078-0432.CCR-12-1092
PMCID: PMC3845832  PMID: 23300276
chronic lymphocytic leukemia; flavopiridol; tumor lysis syndrome; population pharmacokinetics; glucuronide metabolite; logistic regression model
23.  Cyclophosphamide, Alvocidib (Flavopiridol), and Rituximab, a Novel Feasible Chemoimmunotherapy Regimen for Patients with High-Risk Chronic Lymphocytic Leukemia 
Leukemia research  2013;37(10):1195-1199.
Alvocidib has demonstrated efficacy in high-risk chronic lymphocytic leukemia (CLL) patients. In this phase I study, we combined cyclophosphamide, alvocidib and rituximab (CAR) in a schema designed to mitigate tumor lysis syndrome (TLS) seen previously with alvocidib. Nine nucleoside analog-naïve, high-risk patients received escalating doses of CAR therapy. Dose limiting toxicity was not experienced. No instances of TLS were observed. Patient responses included three complete remissions and four partial remissions. CAR was tolerable and active in high-risk CLL patients without TLS toxicity. With continued monitoring of toxicities, a phase Ib/II study of this combination as frontline therapy is warranted.
doi:10.1016/j.leukres.2013.06.006
PMCID: PMC3934299  PMID: 23867058
chronic lymphocytic leukemia; flavopiridol; high-risk cytogenetics; cyclin-dependent kinase inhibitor; chemoimmunotherapy; alvocidib; del(17p); del(11q)
24.  Pharmacokinetics and Dose Escalation of the Heat Shock Protein Inhibitor 17-AAG in Combination with Bortezomib in Relapsed or Refractory Acute Myeloid Leukemia 
Leukemia & lymphoma  2013;54(9):10.3109/10428194.2012.760733.
This phase I study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT) of the heat shock protein 90 (HSP90) inhibitor 17-allyamino-17-demethoxygeldanamycin (17-AAG) in combination with bortezomib, and to provide pharmacokinetic data in relapsed or refractory acute myeloid leukemia (AML). Eleven patients were enrolled. The MTD was 17-AAG 150mg/m2 and bortezomib 0.7mg/m2. Hepatic toxicity and cardiac toxicity were dose limiting. Co-administration on day 4 led to a decrease in clearance (p=0.005) and increase in AUC (p=.032) of 17-amino-17-demethoxygeldanamycin (17-AG) not observed when 17-AAG was administered alone. Pharmacokinetic parameters of patients who developed toxicities and those who did not were not different. The combination of 17-AAG and bortezomib led to toxicity without measurable response in patients with relapsed or refractory AML. Pharmacokinetic data provide insight for studies of related agents in AML; next generation HSP90 inhibitors are appealing for further development in this area.
doi:10.3109/10428194.2012.760733
PMCID: PMC3860322  PMID: 23256542
Relapsed AML; bortezomib; 17-AAG; heat shock protein inhibition
25.  In Vivo Quantification of Active Decitabine-Triphosphate Metabolite: A Novel Pharmacoanalytical Endpoint for Optimization of Hypomethylating Therapy in Acute Myeloid Leukemia 
The AAPS Journal  2012;15(1):242-249.
Decitabine (DAC) is used for treatment of patients with myelodysplastic syndromes and acute myeloid leukemia (AML). Following cellular uptake, DAC is activated to DAC-triphosphate (TP) and incorporated into DNA. Once incorporated into the DNA, DAC-TP binds and inactivates DNA methyltransferases (DNMTs), thereby leading to hypomethylation and re-expression of epigenetically silenced tumor suppressor genes and ultimately antileukemia activity. However, direct evidence of in vivo DAC-TP occurrence in DAC-treated patients has been difficult to demonstrate due to a lack of suitable validated analytical methodology. Thus, we developed and validated a nonradioactive sensitive and specific LC-MS/MS assay for quantification of DAC-TP. The assay is linear from 50 to 1,000 nM and from 1 to 10 μM and has a lower limit of quantitation of 50 nM and a coefficient of variation for both within- and between-day precision <20%. Following DAC treatment, we detected DAC-TP in parental and DAC-resistant AML cells (in vitro) and bone marrow (BM) and spleen of normal and leukemic mice (in vivo). Downregulation of DNMTs and correlation of DAC-TP concentration with proteins involved in mechanisms of DAC resistance were also demonstrated. The clinical applicability of this method was proven by measuring DAC-TP level in BM and blood mononuclear cells from DAC-treated AML patients. Higher levels are seemingly associated with clinical response. Monitoring the DAC-TP intracellular level may serve as a novel pharmacological endpoint for designing more effective DAC-based regimens.
doi:10.1208/s12248-012-9427-5
PMCID: PMC3535094  PMID: 23180159
acute myeloid leukemia; decitabine; metabolite; quantification method; triphosphate

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