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Prepublished online as a Blood First Edition Paper on October 31, 2002; DOI 10.1182/blood-2002-07-1973.
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Leukemia, The University of
Texas MD Anderson Cancer Center, Houston, TX; and Johnson & Johnson
Pharmaceutical Research & Development, Titusville, NJ.
We investigated the clinical activity of the farnesyl
transferase inhibitor R115777 in 22 patients with chronic myelogenous leukemia (CML) in chronic, accelerated, or blastic phase and in 8 patients with myelofibrosis (MF) and 10 patients with multiple myeloma
(MM). R115777 was administered at 600 mg orally twice daily for 4 weeks
every 6 weeks. Seven patients with CML (6 in chronic phase, 1 in
advanced phase) achieved complete or partial hematologic response. Four
of them had a minor cytogenetic response. Responses were transient,
with a median duration of 9 weeks (range, 3-23 weeks). Two patients
discontinued therapy because of toxicity while in complete hematologic
response. Two MF patients had a significant decrease in splenomegaly,
one had normalization of white blood cell count and differential, and
one became transfusion independent. One patient with MM had a reduction
in monoclonal protein of 34%. Adverse events included nausea in 22 patients (55%; all grade 2 or lower) and fatigue in 19 (48%; grade 3 or higher in 1). Other grade 3 or 4 toxicities included skin rash (4 patients, 10%), peripheral neuropathy (2 patients, 5%), and liver
toxicity (2 patients, 5%). Patients who responded to therapy had
significantly higher plasma vascular endothelial growth factor (VEGF)
concentrations prior to treatment than nonresponders. Plasma concentrations decreased significantly during therapy among responders. R115777 showed clinical activity in patients with CML and MF. The
effect on VEGF needs to be further investigated to determine whether
this might be a possible mechanism of action of R115777.
(Blood. 2003;101:1692-1697) The ras family of proto-oncogenes
comprises a group of G-proteins that have the ability to bind guanine
nucleotides.1,2 Ras is synthesized in the cytoplasm as a
precursor protein that requires additional posttranslational
modifications in order to attach to the inner surface of the plasma
membrane, a prerequisite for Ras-mediated signal transduction. These
modifications are accomplished by a prenylation reaction involving the
attachment of a 15-carbon farnesyl group to the C-terminal cysteine
residue. This reaction is mediated by an enzyme called farnesyl protein transferase (FPT).3,4 Alternatively, prenylation may be
accomplished by addition of a 20-carbon geranylgeranyl isoprenoid
mediated by geranylgeranyl-protein transferase (GGPT).
Ras mutations and Ras protein activation are frequent
features of malignant transformation. Approximately 30% of human
cancers have been associated with ras
mutations.5,6 The frequency of ras
mutations varies in hematologic malignancies, from 5% to 15% in acute
lymphoblastic leukemia and up to 65% in chronic myelomonocytic leukemia.2,5,6 Ras activation may occur by mechanisms
other than mutations. A prominent example is activation of Ras by the bcr/abl chimeric gene.7,8 Therefore, inhibition
of Ras activation has been investigated as an antineoplastic
therapy.9 One approach to Ras inhibition is inhibition of
FPT.10-12 R115777 (Zarnestra, Titusville, NJ) is a potent
nonpeptidomimetic FPT inhibitor (FTI) with significant antitumor
effects in preclinical studies.13
In this study, we investigated the activity of R115777 in patients with
Philadelphia chromosome (Ph)-positive chronic myeloid leukemia (CML),
myelofibrosis (MF), or multiple myeloma (MM). Plasma concentrations of
vascular endothelial growth factor (VEGF) have been found to be
elevated in CML,14,15 and increased expression of VEGF
correlates with poor prognosis.15 In addition, one of the
proposed effects of FPT inhibition is suppression of angiogenesis with
decreased expression of VEGF.16 Because of the clinical significance of VEGF in CML, we investigated whether R115777 has any in
vivo effect on VEGF and other angiogenic factors to determine whether
any clinical effect may be mediated through this mechanism.
Patients
Prior to the start of therapy, all patients had a complete
history taken and received a complete physical examination, a complete blood count, SMA-12 (total protein, albumin, calcium,
phosphorus, blood urea nitrogen [BUN], creatinine, glucose, uric
acid, total bilirubin, alkaline phosphatase, lactate dehydrogenase, and
alanine aminotransferase), a bone marrow (BM) aspiration (and
biopsy when indicated), and cytogenetics. The monoclonal
protein spike was measured in patients with multiple myeloma.
All of these studies were repeated periodically while the patient was
receiving treatment.
Treatment schedule
Definitions of response and disease stages AP was defined as the presence of any one of the following: (1) percentage of peripheral blood (PB) or BM blasts 15% or higher; (2) percentage of PB or BM blasts plus promyelocytes 30% or higher; (3) percentage of PB or BM basophils 20% or higher; (4) platelet count lower than 100 × 109/L unrelated to therapy; (5) clonal evolution; or (6) hemoglobin level lower than 7 g/dL unrelated to therapy or bleeding. Blast phase was defined as the presence of 30% or more blasts in the PB or BM or extramedullary disease outside the liver or spleen.Responses in CML were defined as previously reported.17 Briefly, a complete hematologic response (CHR) was defined as WBC count lower than 10 × 109/L, platelet count lower than 450 × 109/L, no immature PB cells (blasts, promyelocytes, myelocytes), and disappearance of all signs and symptoms of leukemia. This was further categorized by the best cytogenetic response: (1) complete: Ph+ 0%; (2) partial: Ph+ 1% to 34%; (3) minor: Ph+ 35% to 90%. A major cytogenetic response included complete plus partial cytogenetic responses (Ph+ less than 35%). Partial hematologic response (PHR) was defined as CHR except for the persistence of immature cells in PB and/or persistent splenomegaly or thrombocytosis (> 450 × 109/L) but at least 50% less than pretreatment. In MM, a complete response (CR) was defined as disappearance of serum and/or urine monoclonal protein on 2 determinations at least 4 weeks apart, with fewer than 5% plasma cells in the BM and PB, resolution of any soft-tissue plasmacytomas present at the start of therapy, and resolution of all signs and symptoms of disease. A partial response (PR) was defined as a reduction of the monoclonal protein by 50% or more on 2 determinations at least 4 weeks apart, reduction in soft-tissue plasmacytoma by 50% or more, and decrease in bone pain from grade 2 to grade 1 or lower. In MF, CR was defined as normalization of the PB for at least 4 weeks, with an absolute neutrophil count of more than 109/L with no immature cells, and platelet count higher than 100 × 109/L. Partial response was considered as the presence of at least 2 of the following: (1) hemoglobin level increase by 2 g/dL or more and to more than 9 g/dL, plus independence from transfusions; (2) platelet count increase by 100% and to more than 50 × 109/L, plus transfusion independence; (3) neutrophil count increase by 100% and to more than 109/L; (4) reduction of splenomegaly by 50%. Laboratory correlative studies Assessment of ras mutations was performed by sequencing. Enzyme-linked immunosorbent assay (ELISA) for VEGF, basic fibroblast growth factor (bFGF), hepatocyte growth factor (HGF), and tumor necrosis growth factor- (TNF-) was performed using commercially available kits from R&D Systems (Minneapolis, MN). We followed the
protocols recommended by the manufacturer. Briefly, plasma was
collected using EDTA (ethylenediaminetetraacetic acid) and stored at  82°C. Patients' plasma samples were added to separate microplates, each containing a specific monoclonal antibody. The mixtures were incubated at room temperature for 2 hours. The plates were washed 3 times to remove any unbound substances. Enzyme-linked polyclonal antibodies specific for each protein were added to the
wells, and mixtures were incubated at room temperature for 2 hours
followed by another washing to remove any unbound antibody or enzyme
reagent. A substrate solution was added to the wells, and a blue color
developed. The intensity of the blue color was proportionate to the
amount of cytokine bound in the initial step. The color development was
stopped, and the intensity of the color was measured and compared with
a standard curve. Reading was done at 450-nm wavelength per the
manufacturer's recommendations.
Statistical analysis The Kruskal-Wallis test was used to compare values between groups.
Between February 2001 and October 2001, 40 patients were treated.
These included 22 patients with CML, 10 with MM, and 8 with MF. The
clinical characteristics of patients by diagnosis are presented in
Table 1. Thirteen patients were
investigated for N- or K-ras mutations; only 1 patient (8%;
CML-BP) had a mutation (K-ras). The results will be
described by disease group.
Chronic myeloid leukemia Twenty-two patients with CML in CP (n = 10), AP (n = 6), or BP (n = 6) were treated. The median time from diagnosis to therapy was 23 months (range, 5-82 months). All patients had received at least one prior therapy for CML besides hydroxyurea, and the median number of prior regimens was 2 (range, 1-4 regimens). Twenty patients (91%) had received prior IFN-; the 2 patients who had not received IFN-
were in BP and had failed other therapies (imatinib mesylate and
troxacitabine, respectively). Two patients received pegylated IFN-
after failing therapy with conventional IFN-. Seventeen patients
(77%) had received imatinib and were resistant, refractory, or
intolerant to it. Six patients had received other investigational
agents, including troxacitabine (n = 2), homoharringtonine plus ara-C
(n = 2), decitabine (n = 1), and oral idarubicin (n = 1); 1 patient had relapsed in AP after an allogeneic bone marrow transplantation.
Patients received R115777 therapy for a median of 8 weeks (range, 1-25 weeks). Seven patients (32%; 95% confidence interval [CI], 0.14-0.55) achieved a complete (n = 5) or partial (n = 2) hematologic response. All but one of the responses occurred among patients in CP. Thus, 6 of 10 patients in CP (60%; 95%CI, 0.26-0.88) responded. All responses occurred in the absence of hydroxyurea and only one patient (PHR) required anagrelide. Among responders, 4 (1 AP, 3 CP) had reductions in the percentage of Ph+ metaphases. Three of these patients achieved a minor cytogenetic response; the fourth started with 90% of metaphases Ph+ and decreased on therapy to 65%. The responses were transient, with a median duration of response of 9 weeks (range, 3-23 weeks). Five patients discontinued therapy because of loss of response and 2 because of toxicity. Two patients had an ongoing CHR (one of them also had a minor cytogenetic response) at the time treatment was discontinued because of toxicity (fatigue and skin rash, respectively). These patients received therapy for 7 and 12 weeks, respectively. All other patients had lost their response at the time they stopped therapy. Eleven patients (50%; CP n = 8, AP n = 3) were alive after a median follow-up of 11 months. The median survival was 42 weeks. Among patients in CP, the median survival has not been reached. Four patients have transformed to accelerated (n = 2) or blastic (n = 2) phase, and 2 of them died after transformation. Myelofibrosis Of the 8 patients with MF, 2 had received therapy with transfusion support only, 3 had received recombinant human erythropoietin (rhEPO) and transfusion support, and 3 had received multiple therapies including hydroxyurea (n = 2), interferon (n = 2), rhEPO, 9-nitrocamptothecin, thalidomide, and anabolic steroids (n = 1 each). Six patients had splenomegaly, with a median of 12.5 cm below the costal margin (BCM) (range, 3-18 cm), and 3 had hepatomegaly of 6, 8, and 15 cm BCM.Four patients received only 1 course of therapy: 2 discontinued therapy
because of toxicity (grade 3 skin rash), 1 was lost to follow-up, and 1 had progression to acute myeloid leukemia (AML). Two patients
were treated for 22 and 28 weeks, respectively, and had a reduction in
spleen size from 18 cm BCM (in both cases) to 9 and 10 cm BCM,
respectively. Both remained packed red blood cell (PRBC)-transfusion
dependent. At the time of writing, 2 patients are still
receiving therapy 24 and 33 weeks after being included in this trial.
One patient had received thalidomide and had become PRBC-transfusion independent with that therapy. However, the
patient developed progressive splenomegaly, with an increase in WBC
count and a differential left shift. Thalidomide was discontinued and R115777 was started. The bone marrow at the time showed extensive myelofibrosis. The spleen decreased in size from 6 cm BCM to
undetectable, the WBC count normalized, and the immature forms
disappeared from the peripheral blood. The patient continues to be
RBC-transfusion independent. The second patient (Figure
1) had received rhEPO and thalidomide,
had not responded, and was requiring RBC transfusions at least once
every week. Two months after the start of therapy, he became
transfusion independent and his platelet count improved from
50 × 109/L to 150 × 109/L. The response
has been sustained after 33 weeks of therapy.
Three patients have died, at 6, 12, and 39 weeks from the start of therapy with R115777. Five patients are alive, with a median follow-up of 32 weeks (range, 22-49 weeks). Multiple myeloma The 10 patients with refractory or relapsed MM had received a median of 4 prior treatment regimens (range, 1-6 regimens), including VAD in 7 patients, thalidomide in 7, and autologous stem cell transplantation in 3. The median time on therapy was 7 weeks (range, 2-14 weeks). The median monoclonal paraprotein spike at the start of therapy was 2.7 g/dL (range, 1.3-6.2 g/dL), compared with 2.9 g/dL (range, 2.1-7.3 g/dL; P = .10) at the end of therapy. One patient had a reduction in monoclonal protein of 34% and one had a reduction of 6%. All others had no change or an increase in monoclonal protein.Six patients died; median time to death was 18.5 weeks (range, 4-48 weeks) from the start of therapy. At the time of writing, 4 patients are alive, with a median follow-up of 41 weeks (range, 12-48 weeks). Toxicity The median duration of therapy was 7 weeks (range, 1-28 weeks). Toxicity is presented in Table 2. Nausea and vomiting were the most common side effects, occurring in 22 patients (55%), but these side effects were always grade 2 or lower and responded to symptomatic treatment. Fatigue was noted in 19 patients (48%) and resulted in discontinuation of therapy in 1 patient (3%) with CML after 12 weeks on therapy while still in CHR with a minor cytogenetic response. The symptoms persisted after a dose reduction to 200 mg administered orally twice daily and finally resolved 4 weeks after treatment was discontinued. Grade 3 or 4 skin rash was noted in 4 patients (10%), including 1 patient with CML who had to discontinue therapy while still in CHR. This side effect in general was in the form of a diffuse, pruritic rash, which recurred upon rechallenge at a lower dose. Peripheral neuropathy grade 3 or 4 was seen in 3 patients (8%) in the form of painful dysesthesias in the lower extremities. Symptoms resolved after discontinuation of the therapy, but one patient developed progressive peripheral neuropathy that had not resolved at the time of her death from progressive disease 3 months after discontinuation of R115777. Hematologic toxicity can more uniformly be assessed among patients who started with normal or high platelets (n = 22) and neutrophils (n = 26), or hemoglobin (n = 11) at the start of therapy. Grade 3 or higher neutropenia was seen in 15 patients (58%), thrombocytopenia in 6 (27%), and anemia in 2 (18%). Twenty-three patients (58%) required dose interruptions and/or reductions because of myelosuppression or extramedullary toxicity.
Effects on angiogenic factors Plasma concentrations of angiogenic factors, including VEGF, bFGF, HGF, and TNF-, were measured at baseline and after 7 and 14 days of
therapy. Sequential evaluation was available for 25 patients (63%): 15 with CML, 6 with MM, and 4 with MF. As previously reported, plasma
concentrations of VEGF, bFGF, and HGF were elevated at baseline among
patients with CML.14 Similar increments were seen among
patients with MM and MF and were not statistically significantly
different compared with patients with CML. Sequential measures did not
show any significant change during the first 2 weeks of therapy (Table
3). However, when the change in VEGF concentrations during the first 14 days of therapy was evaluated for
responders (ie, CML patients with at least a PHR, or myelofibrosis with
hematologic improvement) vs nonresponders, a statistically significant
decline was observed in patients who responded to therapy compared with
those who did not respond (Figure 2). As shown, this difference is mostly attributable to very high baseline concentrations among patients who responded (median, 668.8 pg/mL; range, 28.8-1166.3 pg/mL) compared with nonresponders (median, 78.88 pg/mL; range, 21.2-469.8 pg/mL; P = .009). The only value among responders within the range for healthy individuals as identified in our laboratory14 was for a patient with myelofibrosis;
the median concentration at the start of treatment for patients with CML who responded was 674.9 pg/mL (range, 144.9-1166.3 pg/mL), compared
with 98.6 pg/ml (range, 19.6-1085 pg/mL; P = .001) for nonresponders with CML. There was no significant difference in the
values after 7 and 14 days of therapy between responders and nonresponders. No significant difference was observed in any of the
other angiogenic factors analyzed.
R115777 is a nonpeptidomimetic inhibitor of FPT that has demonstrated activity in patients with acute myeloid leukemia (AML)18 and myelodysplastic syndromes (MDS).19,20 Our study demonstrated its modest activity in patients with CML and MF. No activity was noted in patients with MM. Preclinical studies have demonstrated significant anti-CML activity of FTIs.21,22 Peters et al demonstrated inhibition of proliferation of bcr/abl-transformed BaF3 cells and primary human CML cells after incubation with SCH66336, another nonpeptidomimetic FTI.21 Mice treated with SCH66336 after being injected with bcr/abl-BaF3 cells survived, whereas those who received no treatment after the injection of these cells died within 4 weeks.21 Similar results were obtained in a bcr/abl-positive acute lymphoblastic leukemia murine model using SCH66336.22 In addition, SCH66336 has been reported to overcome resistance to imatinib. Hoover et al reported that SCH66336 inhibited proliferation of imatinib-resistant cell lines and hematopoietic colony formation from patients with CML unresponsive to imatinib,23 and Nakajima et al demonstrated apoptosis induced by SCH66336 in imatinib-resistant cells.24 In this clinical trial, we report demonstrable albeit modest activity in 33% of patients with CML. Most of the responses were transient, but it is possible that therapy may have been discontinued prematurely in some patients. The study allowed for the use of hydroxyurea only for the first 4 weeks, and responding patients were withdrawn (or discontinued) from therapy at the first sign of rising WBC count. This frequently occurred at the end of the periods when R115777 was not taken. Since FTIs are mostly cytostatic, it is reasonable to hypothesize that a more prolonged exposure may be required to demonstrate a sustained response. Thus, alternative schedules, including long-exposure schedules with lower doses, might be preferable and are currently being investigated. Interestingly, we did not observe responses among patients in BP, whereas Karp et al18 reported a partial response in 2 of 2 patients with Ph+ CML in BP. The clinical results reported here with R115777 and the reported synergy with imatinib23,24 provide the basis for ongoing studies combining FTIs and imatinib. The responses observed in patients with MF are intriguing. Although 2 patients showed only modest (but clinically significant) decreases in splenomegaly, 2 patients had a more notable response with normalization of the peripheral blood abnormalities, 1 of them (Figure 1) becoming transfusion independent. R115777 has been reported to have significant in vitro activity in MF with myeloid metaplasia and other myeloproliferative disorders. Concentrations of 5 to 24 nM selectively inhibited the in vitro growth of myeloid and megakaryocytic progenitor colonies obtained from patients with MF, essential thrombocytemia, and polycythemia vera.25 Further exploration of this agent in myeloproliferative disorders is ongoing. The minimal activity in MM was disappointing. In vitro studies have suggested that FTIs may have significant activity in this disease. Bolick et al reported significant activity of FTI-277 in human myeloma cell lines.26 A different FTI, perillic acid, showed significant activity against myeloma cell lines and primary cells from patients while relatively sparing nonmyeloma bone marrow elements.27 Alsina et al recently reported results on 12 evaluable patients with MM treated with this agent.28 Half of the patients had a reduction in the monoclonal protein of less than 25%, compatible with disease stabilization. The dose and schedule used in our trial may not have been ideal and a more prolonged therapy may be required. Alsina et al used a dosage of 300 mg twice daily for 3 weeks, repeated every 4 weeks. Four of the 6 patients with a response were able to stay on therapy for at least 4 cycles (ie, 16 weeks), whereas the median time on treatment for our patients was 7 weeks (range, 2-14 weeks). Therefore, schedules that allow for a more prolonged administration of R115777 should be investigated further. The actual mechanism of action of FTIs is not yet clear. Clinical responses in this trial and others18-20 have been unrelated to Ras mutations. As mentioned earlier, Ras can be activated by other mechanisms. However, farnesylation is not unique to Ras,2,11,29 and Ras-independent mechanisms of cell growth inhibition by FTI, such as gain of RhoB that has been prenylated by GGPT30 and inhibition of the mitotic kinasins CENP-E and CENP-F,31 have been reported. Additionally, Ras can be prenylated by GGPT.2,11,29 Although combinations of FTIs and GGPTase inhibitors may be synergistic,26,32 initial animal studies have resulted in significant toxicity,32 which may be related to the ubiquitous nature of proteins requiring GGPT. Thus, dual inhibition is unlikely to be beneficial in the clinic. One recently proposed mechanism of action of FTIs is through inhibition of angiogenesis. Several investigators have reported that different FTIs inhibit angiogenesis in a variety of models.16,33-36 Ras activation (eg, via mutations) up-regulates VEGF expression,37,38 and inhibition of Ras through FPT inhibition has led to significant decrease in the expression and secretion of VEGF.16,33-36 We have previously reported a significant increase in angiogenesis in patients with acute and chronic leukemias.14 Patients with CML had the highest increase in VEGF plasma concentrations, and increased cellular concentrations of VEGF are associated with an adverse outcome, independent of other prognostic factors.15 These results suggest a possible role of VEGF in the pathogenesis and or progression of CML. In this report, we identified a significant decrease in the plasma concentrations of VEGF among patients who responded to R115777. In addition, patients who responded had a higher baseline VEGF plasma concentration. The sample size studied is small and this observation will require further confirmation in other studies. However, these results showed for the first time in vivo a possible antiangiogenic effect of R115777 and suggest that patients with high concentrations of VEGF might be more likely to respond to this agent. As mentioned, toxicity limited continuation of therapy in several patients, including some having an adequate response. The starting dose selected for this trial was within the maximum tolerated dosage reported in other trials. However, the dosage 600 mg twice daily had not been given on a 4-week schedule. Karp et al,18 using a 21-day schedule, observed dose-limiting toxicities at 1200 mg administered orally twice daily, although dosages of 900 mg administered orally twice daily were associated with frequent dose interruptions. Similarly, Kurzrock et al reported frequent dose interruptions using dosages of 900 mg administered orally twice daily20 in patients with MDS. In both studies, the majority of patients requiring dose interruptions were older than 70 years. However, considering that significant FPT inhibition occurs at dosages of 300 mg twice daily and that no clear correlation existed between dose and response, lower doses may be more desirable, particularly for prolonged therapy. In summary, R115777 used as a single agent had activity of short duration in one third of previously treated CML patients. Considering the preclinical data discussed above, exploration of combination therapy with FTI and imatinib mesylate is warranted in CML. The effect observed on VEGF concentrations is interesting and will need confirmation in a larger population. If these results can be corroborated, the effect on VEGF may suggest a new and important therapeutic target in CML. The data in MF are intriguing, and further investigations in this disease are warranted.
Submitted July 15, 2002; accepted October 5, 2002.
Prepublished online as Blood First Edition Paper, October 31, 2002; DOI 10.1182/blood-2002-07-1973.
Supported in part by grant 2057-01 from the Leukemia and Lymphoma Society (J.C.), research funding from Johnson & Johnson Pharmaceutical Research & Development (J.C. and H.K.), and National Cancer Institute grant 1R21-CA91518A (R.K.). Jorge Cortes is a Clinical Research Scholar for the Leukemia & Lymphoma Society.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Jorge Cortes, Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 428, Houston, TX 77030; e-mail: jcortes{at}mdanderson.org.
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M. Copland, F. Pellicano, L. Richmond, E. K. Allan, A. Hamilton, F. Y. Lee, R. Weinmann, and T. L. Holyoake BMS-214662 potently induces apoptosis of chronic myeloid leukemia stem and progenitor cells and synergizes with tyrosine kinase inhibitors Blood, March 1, 2008; 111(5): 2843 - 2853. [Abstract] [Full Text] [PDF]
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R. Kurzrock, H. M. Kantarjian, M. A. Blascovich, C. Bucher, S. Verstovsek, J. J. Wright, S. R. Pilat, J. E. Cortes, E. H. Estey, F. J. Giles, et al. Phase I Study of Alternate-Week Administration of Tipifarnib in Patients with Myelodysplastic Syndrome Clin. Cancer Res., January 15, 2008; 14(2): 509 - 514. [Abstract] [Full Text] [PDF]
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J.-L. Harousseau, J. E. Lancet, J. Reiffers, B. Lowenberg, X. Thomas, F. Huguet, P. Fenaux, S. Zhang, W. Rackoff, P. De Porre, et al. A phase 2 study of the oral farnesyltransferase inhibitor tipifarnib in patients with refractory or relapsed acute myeloid leukemia Blood, June 15, 2007; 109(12): 5151 - 5156. [Abstract] [Full Text] [PDF]
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P. Fenaux, A. Raza, G. J. Mufti, C. Aul, U. Germing, H. Kantarjian, L. Cripe, R. Kerstens, P. De Porre, and R. Kurzrock A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome Blood, May 15, 2007; 109(10): 4158 - 4163. [Abstract] [Full Text] [PDF]
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M. Raponi, J.-L. Harousseau, J. E. Lancet, B. Lowenberg, R. Stone, Y. Zhang, W. Rackoff, Y. Wang, and D. Atkins Identification of Molecular Predictors of Response in a Study of Tipifarnib Treatment in Relapsed and Refractory Acute Myelogenous Leukemia Clin. Cancer Res., April 1, 2007; 13(7): 2254 - 2260. [Abstract] [Full Text] [PDF]
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H. M. Kantarjian, F. Giles, A. Quintas-Cardama, and J. Cortes Important Therapeutic Targets in Chronic Myelogenous Leukemia Clin. Cancer Res., February 15, 2007; 13(4): 1089 - 1097. [Abstract] [Full Text] [PDF]
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J. E. Lancet, I. Gojo, J. Gotlib, E. J. Feldman, J. Greer, J. L. Liesveld, L. M. Bruzek, L. Morris, Y. Park, A. A. Adjei, et al. A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia Blood, February 15, 2007; 109(4): 1387 - 1394. [Abstract] [Full Text] [PDF]
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A. Quintas-Cardama and J. E. Cortes Chronic Myeloid Leukemia: Diagnosis and Treatment Mayo Clin. Proc., July 1, 2006; 81(7): 973 - 988. [Abstract] [Full Text] [PDF]
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A. Tefferi Pathogenesis of Myelofibrosis With Myeloid Metaplasia J. Clin. Oncol., November 20, 2005; 23(33): 8520 - 8530. [Abstract] [Full Text] [PDF]
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G. Barosi, D. Bordessoule, J. Briere, F. Cervantes, J.-L. Demory, B. Dupriez, H. Gisslinger, M. Griesshammer, H. Hasselbalch, R. Kusec, et al. Response criteria for myelofibrosis with myeloid metaplasia: results of an initiative of the European Myelofibrosis Network (EUMNET) Blood, October 15, 2005; 106(8): 2849 - 2853. [Abstract] [Full Text] [PDF]
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J. Cortes and H. Kantarjian New Targeted Approaches in Chronic Myeloid Leukemia J. Clin. Oncol., September 10, 2005; 23(26): 6316 - 6324. [Abstract] [Full Text] [PDF]
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N. M.G.M. Appels, J. H. Beijnen, and J. H.M. Schellens Development of Farnesyl Transferase Inhibitors: A Review Oncologist, September 1, 2005; 10(8): 565 - 578. [Abstract] [Full Text] [PDF]
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R. Buzzeo, S. Enkemann, R. Nimmanapalli, M. Alsina, M. G. Lichtenheld, W. S. Dalton, and D. M. Beaupre Characterization of a R115777-Resistant Human Multiple Myeloma Cell Line with Cross-Resistance to PS-341 Clin. Cancer Res., August 15, 2005; 11(16): 6057 - 6064. [Abstract] [Full Text] [PDF]
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P. Bachireddy, P. K. Bendapudi, and D. W. Felsher Getting at MYC through RAS Clin. Cancer Res., June 15, 2005; 11(12): 4278 - 4281. [Full Text] [PDF]
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V. Papadimitrakopoulou, S. Agelaki, H. T. Tran, M. Kies, R. Gagel, R. Zinner, E. Kim, G. Ayers, J. Wright, and F. Khuri Phase I Study of the Farnesyltransferase Inhibitor BMS-214662 Given Weekly in Patients with Solid Tumors Clin. Cancer Res., June 1, 2005; 11(11): 4151 - 4159. [Abstract] [Full Text] [PDF]
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J. Cortes, S. Faderl, E. Estey, R. Kurzrock, D. Thomas, M. Beran, G. Garcia-Manero, A. Ferrajoli, F. Giles, C. Koller, et al. Phase I Study of BMS-214662, a Farnesyl Transferase Inhibitor in Patients With Acute Leukemias and High-Risk Myelodysplastic Syndromes J. Clin. Oncol., April 20, 2005; 23(12): 2805 - 2812. [Abstract] [Full Text] [PDF]
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D. Ferguson, L. E. Rodriguez, J. P. Palma, M. Refici, K. Jarvis, J. O'Connor, G. M. Sullivan, D. Frost, K. Marsh, J. Bauch, et al. Antitumor Activity of Orally Bioavailable Farnesyltransferase Inhibitor, ABT-100, Is Mediated by Antiproliferative, Proapoptotic, and Antiangiogenic Effects in Xenograft Models Clin. Cancer Res., April 15, 2005; 11(8): 3045 - 3054. [Abstract] [Full Text] [PDF]
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P. F. Lebowitz, J. Eng-Wong, B. C. Widemann, F. M. Balis, N. Jayaprakash, C. Chow, G. Clark, S. B. Gantz, D. Venzon, and J. Zujewski A Phase I Trial and Pharmacokinetic Study of Tipifarnib, a Farnesyltransferase Inhibitor, and Tamoxifen in Metastatic Breast Cancer Clin. Cancer Res., February 1, 2005; 11(3): 1247 - 1252. [Abstract] [Full Text] [PDF]
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T. M. Zimmerman, H. Harlin, O. M. Odenike, S. Berk, E. Sprague, T. Karrison, W. Stock, R. A. Larson, M. J. Ratain, and T. F. Gajewski Dose-Ranging Pharmacodynamic Study of Tipifarnib (R115777) in Patients With Relapsed and Refractory Hematologic Malignancies J. Clin. Oncol., December 1, 2004; 22(23): 4816 - 4822. [Abstract] [Full Text] [PDF]
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R. A. Mesa, J. K. Camoriano, S. M. Geyer, S. H. Kaufmann, C. E. Rivera, C. Erlichman, and A. Tefferi A Phase 2 Consortium (P2C) Trial of R115777 (Tipifarnib) in Myelofibrosis with Myeloid Metaplasia. Blood (ASH Annual Meeting Abstracts), November 16, 2004; 104(11): 1509 - 1509. [Abstract]
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J. V. Heymach, D. H. Johnson, F. R. Khuri, H. Safran, L. L. Schlabach, F. Yunus, R. F. DeVore III, P. M. De Porre, H. M. Richards, X. Jia, et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer Ann. Onc., August 1, 2004; 15(8): 1187 - 1193. [Abstract] [Full Text] [PDF]
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T. Hideshima, P. L. Bergsagel, W. M. Kuehl, and K. C. Anderson Advances in biology of multiple myeloma: clinical applications Blood, August 1, 2004; 104(3): 607 - 618. [Abstract] [Full Text] [PDF]
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E. Van Cutsem, H. van de Velde, P. Karasek, H. Oettle, W.L. Vervenne, A. Szawlowski, P. Schoffski, S. Post, C. Verslype, H. Neumann, et al. Phase III Trial of Gemcitabine Plus Tipifarnib Compared With Gemcitabine Plus Placebo in Advanced Pancreatic Cancer J. Clin. Oncol., April 15, 2004; 22(8): 1430 - 1438. [Abstract] [Full Text] [PDF]
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R. Kurzrock, M. Albitar, J. E. Cortes, E. H. Estey, S. H. Faderl, G. Garcia-Manero, D. A. Thomas, F. J. Giles, M. E. Ryback, A. Thibault, et al. Phase II Study of R115777, a Farnesyl Transferase Inhibitor, in Myelodysplastic Syndrome J. Clin. Oncol., April 1, 2004; 22(7): 1287 - 1292. [Abstract] [Full Text] [PDF]
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S. M. Sebti Blocked Pathways: FTIs Shut Down Oncogene Signals Oncologist, December 1, 2003; 8(90003): 30 - 38. [Abstract] [Full Text] [PDF]
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J. E. Lancet and J. E. Karp Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy Blood, December 1, 2003; 102(12): 3880 - 3889. [Abstract] [Full Text] [PDF]
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N. Ochiai, R. Uchida, S.-i. Fuchida, A. Okano, M. Okamoto, E. Ashihara, T. Inaba, N. Fujita, H. Matsubara, and C. Shimazaki Effect of farnesyl transferase inhibitor R115777 on the growth of fresh and cloned myeloma cells in vitro Blood, November 1, 2003; 102(9): 3349 - 3353. [Abstract] [Full Text] [PDF]
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N. W. C. J. van de Donk, M. M. J. Kamphuis, B. van Kessel, H. M. Lokhorst, and A. C. Bloem Inhibition of protein geranylgeranylation induces apoptosis in myeloma plasma cells by reducing Mcl-1 protein levels Blood, November 1, 2003; 102(9): 3354 - 3362. [Abstract] [Full Text] [PDF]
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S. S. Clark, L. Zhong, D. Filiault, S. Perman, Z. Ren, M. Gould, and X. Yang Anti-Leukemia Effect of Perillyl Alcohol in Bcr/Abl-Transformed Cells Indirectly Inhibits Signaling through Mek in a Ras- and Raf-Independent Fashion Clin. Cancer Res., October 1, 2003; 9(12): 4494 - 4504. [Abstract] [Full Text] [PDF]
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J. Kuroda, S. Kimura, H. Segawa, Y. Kobayashi, T. Yoshikawa, Y. Urasaki, T. Ueda, F. Enjo, H. Tokuda, O. G. Ottmann, et al. The third-generation bisphosphonate zoledronate synergistically augments the anti-Ph+ leukemia activity of imatinib mesylate Blood, September 15, 2003; 102(6): 2229 - 2235. [Abstract] [Full Text] [PDF]
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C. Selleri, J. P. Maciejewski, N. Montuori, P. Ricci, V. Visconte, B. Serio, L. Luciano, and B. Rotoli Involvement of nitric oxide in farnesyltransferase inhibitor-mediated apoptosis in chronic myeloid leukemia cells Blood, August 15, 2003; 102(4): 1490 - 1498. [Abstract] [Full Text] [PDF]
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B. J. Druker Overcoming Resistance to Imatinib by Combining Targeted Agents Mol. Cancer Ther., March 1, 2003; 2(3): 225 - 226. [Full Text] [PDF]
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J. L. Spivak, G. Barosi, G. Tognoni, T. Barbui, G. Finazzi, R. Marchioli, and M. Marchetti Chronic Myeloproliferative Disorders Hematology, January 1, 2003; 2003(1): 200 - 224. [Abstract] [Full Text] [PDF]
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Abstract
Introduction
