William Plunkett

University of Texas MD Anderson Cancer Center, Houston, Texas, United States

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Publications (326)2232.54 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Accurate identification of patients likely to achieve long-term disease-free survival after chemoimmunotherapy is essential given the availability of less toxic alternatives, such as ibrutinib. Fludarabine, Cyclophosphamide and Rituximab (FCR) achieved a high initial response rate, but continued relapses were seen in initial reports. We reviewed the results of the original 300 patient phase II FCR study, to identify long-term disease-free survivors. MRD was assessed post-treatment by a PCR-based ligase chain reaction assay (sensitivity at least 0.01%). At the median follow-up of 12.8 years, PFS was 30.9% (median PFS 6.4 years). 12.8-year PFS was 53.9% for patients with mutated IGHV gene (IGHV-M) and 8.7% for patients with unmutated IGHV (IGHV-UM). 50.7% of patients with IGHV-M achieved MRD-negativity post-treatment; of these patients, PFS was 79.8% at 12.8 years. A plateau was seen on the PFS curve in patients with IGHV-M, with no relapses beyond 10.4 years in 42 patients (total 105.4 patient-years of follow-up). On multivariable analysis, IGHV-UM [HR 3.37 (2.18-5.21), p<0.001] and del(17p) by conventional karyotyping [HR 7.96 (1.02-61.92), p=0.048] were significantly associated with inferior PFS. Fifteen patients with IGHV-M had 4-color MRD flow cytometry (sensitivity at least 0.01%) performed in peripheral blood, at a median of 12.8 years post-treatment (range 9.5-14.7). All were MRD-negative. The high rate of very long term PFS in patients with IGHV-M after FCR argues for the continued use of chemoimmunotherapy in this patient subgroup outside of clinical trials. In contrast, alternative strategies may be preferred in patients with IGHV-UM, to limit long-term toxicity.
    Blood 10/2015; DOI:10.1182/blood-2015-09-667675 · 10.45 Impact Factor
  • Xiaojun Liu · Yingjun Jiang · Billie Nowak · Dariya Tikhomirova · William Plunkett ·

    Cancer Research 08/2015; 75(15 Supplement):2551-2551. DOI:10.1158/1538-7445.AM2015-2551 · 9.33 Impact Factor
  • Muthana Al Abo · Xiaojun Liu · William Plunkett · Yves Pommier ·

    Cancer Research 08/2015; 75(15 Supplement):2549-2549. DOI:10.1158/1538-7445.AM2015-2549 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):1765-1765. DOI:10.1158/1538-7445.AM2015-1765 · 9.33 Impact Factor
  • Yingjun Jiang · Xiaojun Liu · William Plunkett ·

    Cancer Research 08/2015; 75(15 Supplement):2550-2550. DOI:10.1158/1538-7445.AM2015-2550 · 9.33 Impact Factor
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    ABSTRACT: There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.
    Physical Biology 12/2014; 11(6):065002. DOI:10.1088/1478-3975/11/6/065002 · 2.54 Impact Factor
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    ABSTRACT: While fludarabine, cyclophosphamide and rituximab (FCR) is established as standard first-line treatment for younger patients with chronic lymphocytic leukemia (CLL), there is little information to guide the management of patients with CLL refractory to, or relapsed following, frontline FCR treatment. In order to define optimal salvage strategy, and in order to identify patients not suitable for retreatment with FCR, we examined the survival and treatment outcome of 300 patients enrolled on a phase II study of FCR. After a median 142 months of follow-up, 156 patients developed progressive CLL, with a median survival of 51 months following disease progression. The duration of first remission (REM1) was a key determinant of survival following disease progression and first salvage. Patients with a short REM1 (< 3 years) had short survival irrespective of salvage therapy received; these patients have high unmet medical need and are good candidates for investigation of novel therapies. In patients with a long REM1 (≥ 3 years), salvage treatment with either repeat FCR or lenalidomide-based therapy results in subsequent median survival exceeding 5 years; for these patients, FCR rechallenge represents a reasonable standard of care.
    Blood 10/2014; 124(20). DOI:10.1182/blood-2014-06-583765 · 10.45 Impact Factor
  • Yingjun Jiang · Xiaojun Liu · Adrienne Chestang · William Plunkett ·

    Cancer Research 10/2014; 74(19 Supplement):5454-5454. DOI:10.1158/1538-7445.AM2014-5454 · 9.33 Impact Factor

  • Cancer Research 10/2014; 74(19 Supplement):343-343. DOI:10.1158/1538-7445.AM2014-343 · 9.33 Impact Factor
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    ABSTRACT: 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.
    Oncotarget 06/2014; 6(5). DOI:10.18632/oncotarget.2096 · 6.36 Impact Factor
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    ABSTRACT: Background. The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy. Methods. We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC. Results. Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival. Conclusion. Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints. Trial registration. Clinicaltrials.gov NCT01276613.
    The Journal of clinical investigation 03/2014; 124(4). DOI:10.1172/JCI73455 · 13.22 Impact Factor
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    Varsha Gandhi · William Plunkett · Jorge E Cortes ·
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    ABSTRACT: Chronic myelogenous leukemia (CML) is driven by the Bcr-Abl fusion protein which is a result of a (9;22) chromosomal translocation. Imatinib, dasatinib, and nilotinib (tyrosine kinase inhibitors, TKIs) have revolutionized how CML is treated. While the majority of patients respond to these kinase inhibitors, a subset become resistant to these therapeutics. Synribo (omacetaxine mepesuccinate) was recently FDA approved for Philadelphia-positive CML either in chronic or accelerated phase whose disease failed two prior TKIs. With omacetaxine 1.25 mg/m2 twice daily for 14 days during induction and for 7 days during maintenance, a major cytogenetic response occurred in 20% of patients in chronic phase and major hematologic response in 27% of patients in accelerated phase. Laboratory investigations unraveled the mechanism of action and effectiveness of this agent. Bcr-Abl protein is intrinsically programmed to turn over with a short half-life which makes it susceptible to protein translation inhibitors. Omacetaxine (homoharringtonine) inhibits total protein biosynthesis by binding to A-site cleft of ribosomes. As a corollary to this action, there is a diminution of short-lived proteins such as Bcr-Abl followed by cell death. Approval of this first-in-class protein translation inhibitor opens up new avenues for its use in other diseases as well as mechanism-based combinations.
    Clinical Cancer Research 02/2014; 20(7). DOI:10.1158/1078-0432.CCR-13-1283 · 8.72 Impact Factor
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    ABSTRACT: The combination of cytarabine and fludarabine was associated with superior clinical outcomes compared with those of high-dose cytarabine in relapse acute myeloid leukemia (AML). We conducted a phase I study combining oxaliplatin with cytarabine and fludarabine therapy for patients with relapsed or refractory AML. Between January 2008 and November 2009, 27 patients were registered in the study. Patients had histologically confirmed disease, performance status 0 to 2, and adequate organ function. The treatment regimen consisted of increasing doses of oxaliplatin (25, 30, or 35 mg/m(2)/d) on days 1 to 4 (escalation phase), and fludarabine (30 mg/m²) and cytarabine (500 mg/m²) on days 2 to 6, every 28 days for ≤ 6 cycles. The dose-limiting toxicity was defined as any symptomatic grade ≥ 3 nonhematologic toxicity lasting ≥ 3 days and involving a major organ system. Of 27 patients, 12 were treated in the dose-escalation phase and 15 at the maximum tolerated dose for oxaliplatin (30 mg/m²; expansion phase). All patients were evaluable for toxicity and response. Only 1 patient received the second cycle; the remaining patients received no further study treatment, owing to slow recovery from toxicities or physician decision. Grade 3-4 drug-related toxicities included diarrhea (grade 4) and elevated levels of bilirubin (grade 3) and aspartate transaminase (grade 3). In all, 3 patients had a complete remission and 2 patients complete response without platelet recovery. Oxaliplatin, cytarabine, and fludarabine therapy had antileukemic activity in patients with poor-risk AML, but it was associated with toxicity. Different schedules and doses may be better tolerated.
    Clinical lymphoma, myeloma & leukemia 02/2014; 14(5). DOI:10.1016/j.clml.2014.01.009 · 2.02 Impact Factor
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    ABSTRACT: Clofarabine is a nucleoside analogue with activity in children with acute lymphoblastic leukemia (ALL). Based on the hypothesis that clofarabine inhibits DNA repair after exposure to DNA-damaging agents, we designed a phase I and extension study to evaluate the combination of clofarabine and cyclophosphamide in adult patients with relapsed/refractory ALL. The continual reassessment method (CRM) was used to define the maximum tolerated dose (MTD). Fifty patients with a median age of 30 years (range, 21-72 years) were enrolled, 30 of whom were part of the phase I group. Clofarabine 40 mg/m(2) intravenously daily × 3 days and cyclophosphamide 200 mg/m(2) intravenously every 12 hours × 3 days were established as the MTDs. Dose limiting toxicity (DLT) included diarrhea, transaminase elevations, and skin rashes. The response rate of the whole study group was 14%, including 10% of patients who achieved complete remission (CR) or CR without platelet recovery (CRp). Three responses occurred in patients with primary refractory disease. Early mortality (< 30 days) was 6%. The median duration of response was 69 days (range, 5-315 days). Median overall survival was about 3 months. Compared with day 1 (cyclophosphamide alone), H2AX phosphorylation was increased on day 2 when clofarabine and cyclophosphamide were administered as a couplet (n = 8). The combination of clofarabine plus cyclophosphamide at the doses used in this study in a group of heavily pretreated patients with ALL is only moderately effective. Other doses, alternative schedules, or a more favorable patient population may achieve better results.
    Clinical lymphoma, myeloma & leukemia 12/2013; 14(3). DOI:10.1016/j.clml.2013.12.001 · 2.02 Impact Factor
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    ABSTRACT: Background: Ribonucleotide reductase catalyzes an essential step in the cellular production of deoxyribonucleotide triphosphates and has been associated with clinical outcome in cancer patients receiving nucleoside analog-based chemotherapy. Materials & methods: In the current study, we sequenced the genes RRM1 and RRM2 in genomic DNA from HapMap cell lines with European (Utah residents with northern and western European ancestry [CEU]; n = 90) or African (Yoruba people in Ibadan, Nigeria [YRI]; n = 90) ancestry. Results: We identified 44 genetic variants including eight coding SNPs in RRM1 and 15 SNPs including one coding SNP in RRM2. RRM1 and RRM2 mRNA expression levels were significantly correlated with each other in both CEU and YRI lymphoblast cell lines, and in leukemic blasts from acute myeloid leukemia (AML) patients (AML97, n = 89; AML02, n = 187). Additionally, RRM1 expression was higher among patient features indicative of a high relapse hazard. We evaluated SNPs within the RRM1 and RRM2 genes in the HapMap lymphoblast cell lines from CEU and YRI panels for association with expression and cytarabine chemosensitivity. SNPs of potential significance were further evaluated in AML patients. RRM1 SNPs rs1042919 (which occurs in linkage disequilbrium with multiple other SNPs) and promoter SNP rs1561876 were associated with intracellular 1-β-D-arabinofuranosyl-CTP levels, response after remission induction therapy, risk of relapse and overall survival in AML patients receiving cytarabine and cladribine. Conclusion: These results suggest that SNPs within ribonucleotide reductase might be helpful predictive markers of response to nucleoside analogs and should be further validated in larger cohorts.
    Pharmacogenomics 09/2013; 14(12):1449-66. DOI:10.2217/pgs.13.131 · 3.22 Impact Factor

  • Cancer Research 08/2013; 73(8 Supplement):3528-3528. DOI:10.1158/1538-7445.AM2013-3528 · 9.33 Impact Factor
  • Xiaojun Liu · Billie Nowak · Yingjun Jiang · Walter Hittelman · William Plunkett ·

    Cancer Research 08/2013; 73(8 Supplement):3418-3418. DOI:10.1158/1538-7445.AM2013-3418 · 9.33 Impact Factor
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    ABSTRACT: Akt, a serine/threonine protein kinase, is constitutively phosphorylated and hyperactivated in multiple cancers, including acute myeloid leukemia. High levels are linked to poor survival and inferior responses to chemotherapy, making Akt inhibition an attractive therapeutic target. In this phase I/II study of TCN-PM, a small-molecule Akt inhibitor, TCN-PM therapy was well tolerated in patients with advanced hematological malignancies, and reduced levels of phosphorylation of Akt and its substrate Bad were shown, consistent with inhibition of this survival pathway and induction of cell death. Further investigation of TCN-PM alone or in combination in patients with high Akt levels is warranted.
    Leukemia research 08/2013; 37(11). DOI:10.1016/j.leukres.2013.07.034 · 2.35 Impact Factor
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    ABSTRACT: To improve outcomes of patients with Richter syndrome (RS) and relapsed/refractory chronic lymphocytic leukemia (CLL), we modified the OFAR1 regimen (oxaliplatin and cytarabine doses of the oxaliplatin, fludarabine, cytarabine, and rituximab) for this phase I-II study (OFAR2). OFAR2 consisted of oxaliplatin at 30 mg/m(2) on days 1 to 4, fludarabine at 30 mg/m(2), cytarabine at 0.5 g/m(2), rituximab at 375 mg/m(2) on day 3, and pegfilgrastim at 6 mg on day 6. Fludarabine and cytarabine were given on days 2 and 3 (cohort 1), days 2 to 4 (cohort 2), or days 2 to 5 (cohort 3) every 4 weeks. Phase II followed the "3 + 3" design of phase I. The 102 patients (CLL, 67; RS, 35) treated had heavily pretreated high-risk disease. Twelve patients were treated in phase I; cohort 2 was the phase II recommended dose. The most common toxicities were hematologic. Response rates (phase II) were 38.7% for RS (complete response [CR], 6.5%) and 50.8% for relapsed/refractory CLL (CR, 4.6%). The median survival durations were 6.6 (RS) and 20.6 (CLL) months. Among 9 patients who underwent allogeneic stem cell transplantation (SCT) as post-remission therapy, none has died (median follow-up, 15.9 months). OFAR2 had significant antileukemic activity in RS and relapsed/refractory CLL. Patients undergoing SCT as post-remission therapy had favorable outcomes.
    Clinical lymphoma, myeloma & leukemia 06/2013; 13(5). DOI:10.1016/j.clml.2013.03.012 · 2.02 Impact Factor
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    ABSTRACT: BACKGROUND: Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. METHODS: In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. RESULTS: Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16-59) in group A, 10% (2-33) in group B, and 30% (13-54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. INTERPRETATION: Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. FUNDING: Cyclacel Limited.
    The Lancet Oncology 10/2012; 13(11). DOI:10.1016/S1470-2045(12)70436-9 · 24.69 Impact Factor

Publication Stats

16k Citations
2,232.54 Total Impact Points


  • 1977-2014
    • University of Texas MD Anderson Cancer Center
      • • Department of Leukemia
      • • Department of Experimental Therapeutics
      • • Department of Clinical Investigations
      • • Department of Medical Oncology
      Houston, Texas, United States
    • University of Colorado Hospital
      Denver, Colorado, United States
  • 1986-2010
    • University of Houston
      Houston, Texas, United States
  • 1981-2010
    • University of Texas Health Science Center at Houston
      • Graduate School of Biomedical Sciences
      Houston, Texas, United States
  • 2000
    • Duke University
      Durham, North Carolina, United States