Annals of Oncology Advance Access originally published online on September 13, 2006
Annals of Oncology 2007 18(1):116-121; doi:10.1093/annonc/mdl316
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© 2006 European Society for Medical Oncology
hematologic malignancies |
A phase II study of bortezomib in mantle cell lymphoma: the National Cancer Institute of Canada Clinical Trials Group trial IND.150
1 Department of Medical Oncology, Cross Cancer Institute, Edmonton, Alberta
2 Juravinski Cancer Centre, Hamilton, Ontario
3 University Health Network, Princess Margaret Hospital, Toronto, Ontario
4 BC Cancer Agency, Vancouver Clinic, Vancouver, British Columbia
5 National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada
6 Cancer Therapy Evaluation Program, National Cancer Institute United States, Bethesda, MD, USA
* Correspondence to: Dr E. A. Eisenhauer, Director, IND Program, National Cancer Institute of Canada Clinical Trials Group, Queen's University, 10 Stuart Street, Kingston, Ontario K7L 3N6, Canada. Tel: +1 613 533 6430; Fax: +1 613 533 2411. E-mail: eeisenhauer{at}ctg.queensu.ca
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Abstract |
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Background: We evaluated the activity and toxic effects of bortezomib in patients with mantle cell lymphoma.
Patients and methods: Thirty patients, including 29 eligible patients, were enrolled; 13 had received no prior chemotherapy. The dose of bortezomib was 1.3 mg/m2 given on days 1, 4, 8 and 11 every 21 days. Response was assessed according to the International Workshop Criteria for non-Hodgkin's lymphoma and toxicity graded using the National Cancer Institute Common Toxicity Criteria version 2.0.
Results: There were 13 responding patients (46.4%; 95% confidence interval = 27.5% to 66.1%), including one unconfirmed complete remission. The median response duration was 10 months. Response rates were similar in previously untreated (46.2%) and treated (46.7%) patients. Neurological toxicity and myalgia led to treatment discontinuation in 10 patients after two to seven treatment cycles. Five serious adverse events (including two deaths) associated with fluid retention were observed in the first 12 patients. We subsequently excluded patients with baseline effusions, dyspnea or edema; no further events were seen.
Conclusions: Bortezomib is active in treating patients with mantle cell lymphoma. While cumulative neuromuscular toxic effects limited therapy duration and specific issues related to fluid retention require further evaluation, continued study of this drug in combination regimens is warranted.
Key words: Bortezomib, mantle cell lymphoma
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Mantle cell lymphoma comprises 6% of patients of non-Hodgkin's lymphoma [1, 2] and is currently considered incurable, with a median survival of 3–4 years [3–6]. The need for new treatment strategies has led to a search for new molecular targets. This disease is characterized by overexpression of cyclin D1 as a consequence of the disease defining chromosomal translocation t(11;14)(q13;q32) [7]. Nuclear factor kappa B (NF-
B), which stimulates cyclin D1 expression, also plays a key role in the growth and survival of mantle cell lymphoma cells [8]. In vitro inhibition of NF-B by the proteasome inhibitor bortezomib leads to cell cycle arrest and apoptosis in mantle cell lymphoma cells [8]. Bortezomib showed substantial cytotoxicity against a broad range of human tumors in the NCI in vitro screen [9], and a phase I trial testing bortezomib in patients with refractory hematologic malignancies identified objective responses in patients with myeloma as well as mantle cell and follicular lymphomas [10]. On the basis of these promising preclinical and phase I data, bortezomib was tested in relapsed multiple myeloma using the schedule of 1.3 mg/m2 on days 1, 4, 8 and 11 every 21 days [11]. Positive results of this, and subsequent studies evaluating this dose [12], led to broad regulatory approval of bortezomib for the treatment of myeloma. Therefore, in 2002, the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) selected this dose and schedule of bortezomib for a phase II study evaluating the response rate and toxicity in patients with newly diagnosed or relapsed mantle cell lymphoma. |
patients and methods |
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patient eligibility
Patients were accrued from participating centers of the NCIC CTG. This study was approved by the research ethics boards of the participating institutions and all patients gave written informed consent before registration. Patients were eligible if they were 18 years or older and had previously untreated or relapsed mantle cell lymphoma with no more than two previous courses of treatment. Central pathologic review, including immunochemistry for CD5 and cyclin D1, was undertaken (by RDG) to confirm the diagnosis. Patients were required to have bidimensionally measurable disease, an Eastern Cooperative Oncology Group performance status [13] of 0–2 and no central nervous system (CNS) involvement. In previously treated patients, at least 6 weeks had to elapse from the last dose of chemotherapy and 4 weeks since the completion of radiation treatment. Organ function eligibility was defined as follows: an absolute granulocyte count (ANC) of at least 1.5 x 109/l, platelets of at least 75 x 109/l, serum creatinine and bilirubin no more than 1.5 times the upper limit of normal, an aspartate aminotransferase of no more than 2.5 times the upper limit of normal and adequate cardiac function defined by an ejection fraction measured by echocardiography or radionuclide scan of 45% or greater. Patients were ineligible if they had documented progression while receiving previous chemotherapy regimen, if they had received prior high-dose chemotherapy and stem cell transplantation or if they had received previous therapy with radioactive mAbs. Prior rituximab therapy was allowed. Patients could not have uncontrolled infection, have other serious comorbid disease or be pregnant or lactating. Patients with pleural effusions, ascites or peripheral edema grade 2 or greater were excluded by protocol amendment after 12 patients were accrued (see Results). Baseline studies included computed tomography (CT) of the chest, abdomen and pelvis within 3 weeks before study enrollment, as well as complete blood chemistry and hematology. Bone marrow studies were optional unless a biopsy had never been previously done.
treatment plan
Bortezomib (NSC 681239; PS-341; VELCADE®) was supplied by the Cancer Therapy Evaluation Program (CTEP), NCI United States. It was given i.v. in a dose of 1.3 mg/m2 by bolus injection for 3–5 seconds on days 1, 4, 8 and 11 of a 21-day cycle. Treatment was to begin within five working days of registration and was administered either Monday and Thursday or Tuesday and Friday each of the given treatment weeks. Routine antiemetic or antidiarrheal premedications were not given but premedication for nausea could be added in subsequent cycles if it developed in cycle 1. Only nonsteroid antiemetics were permitted since the use of steroid antiemetic therapy could potentially confuse the interpretation of lymphoma response.
Vital signs were monitored during bortezomib therapy every 15 minutes, beginning at the start of infusion until 30 minutes after treatment and, if blood pressure fell, monitoring continued until recovery. Doses were to be reduced to 1.1 and then 0.9 mg/m2 for hematologic and other adverse events. If toxic effects resulted in more than two dose reductions, the patient discontinued protocol therapy and was treated at the discretion of the investigator.
For hematologic toxicity, the dose adjustments were based on blood count nadirs from the preceding cycle as well as on day 1 and day 8 counts. The dose was reduced if the ANC nadir was <0.5 x 109/l or platelets were <25 x 109/l in the preceding cycle, and treatment was delayed if day 1 ANC was <1.5 x 109/l or platelets were <75 x 109/l. If on day 8 the ANC was <0.75 x 109/l or platelets were <50 x 109/l, the day 8 and day 11 treatments were withheld and treatment resumed on day 1 of the next cycle.
Oral loperamide was prescribed for diarrhea management. If grade 3 or greater diarrhea was documented, the next cycle of bortezomib was reduced by one dose level. If grade 2 neurotoxicity developed, bortezomib doses were reduced by one level to complete the cycle and for future cycles. For grade 3 or greater neurotoxicity, the patient discontinued bortezomib. Following a protocol amendment for fluid retention-related adverse events (see below), dose adjustments for edema were added: for grade 2 or greater edema, the drug was withheld until the basis of the fluid retention was established. If progressive malignancy was the cause of the edema, the patient stopped protocol therapy. If edema was not on the basis of malignancy and was not greater than grade 2, treatment could be continued at the next lower dose level. As part of this same amendment, patients who developed new ascites or effusions on treatment were removed from protocol therapy.
Clinical examination, performance status and lymph node measurements were documented every 3 weeks. Patients were required to have a complete blood count and differential count on days 1, 8 and 15 of each cycle and complete blood chemistry on day 1 of each cycle. After five of the first 12 patients enrolled developed serious adverse events (SAEs) related to fluid retention or edema, the protocol was amended to require cardiac imaging and a 24-hour urine collection for protein every two cycles. Response assessment by CT of the chest, abdomen and pelvis was done every two cycles and a bone marrow biopsy was to be repeated only if complete response (CR) was documented in other sites of disease.
outcome assessment
All patients receiving at least one cycle of therapy were considered assessable for response and all patients receiving at least one dose of bortezomib were assessable for toxicity. Response was classified according to the definitions recommended by the International Workshop to Standardize Response Criteria for non-Hodgkin's lymphomas [14]. Nonmeasurable disease (e.g. pleural effusion, ascites, bone marrow involvement) was not considered in response assessments except in the instance of a new disease (progression) or disappearance (CR). Relapse was determined after a CR when new disease was identified. In patients with unconfirmed complete response (CRu), partial response (PR) or stable disease (SD), relapse was defined as an increase from the nadir of at least 50% in the products of the diameter of any previously identified individual abnormal nodes or with the appearance of any new lesions. Response duration was measured from the time measurement criteria were first met until disease relapse. SD duration was measured from the time of start of therapy until disease relapse.
Therapy was to continue for two cycles after the criteria for CR were first met. Patients with a PR were to continue receiving therapy until progression or for two cycles after documentation of stable PR (i.e. no further tumor shrinkage). Patients with SD continued therapy for a maximum of four cycles (12 weeks) at which time they discontinued protocol therapy. Those patients with disease progression stopped bortezomib when progression was documented and received treatment at the discretion of their attending physician. Toxic effects were evaluated throughout treatment using the NCI Common Toxicity Criteria version 2.0 [15].
statistical considerations
This trial was undertaken before any abstracts or publications of other studies of evaluating bortezomib in mantle cell lymphoma patients were published and thus was designed with conservative assumptions about the possible activity of the agent in this disease. A two-stage trial design [16] was used with objective response as the primary end point. A response rate of 20% or greater was considered of interest for further study, whereas a response rate of <5% would be interpreted as being of little interest. In the first stage, 14 patients were to be enrolled; the observation of at least one response in this group would lead to the enrollment of an additional 16 patients for a planned total of 30 patients. The estimated power of this design was 0.86, when the true response probability is 20%, given a type I error of 0.057.
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results |
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Thirty patients were registered from October 2002 to July 2004. The median age of patients was 67 years (range 48–79) and 72% were male (Table 1). One patient did not have an original tissue block available for review, but was considered eligible on the basis of the review of an original pathology report. Pathology review was undertaken in the remaining 29 patients. Of these, one was ineligible due to concomitant diagnosis of adenocarcinoma. All the 28 remaining reviewed patients expressed cyclin D1 and CD5 by immunohistochemistry. Histology was diffuse in 17 patients, nodular in seven patients and blastoid in two patients. One patient had mantle zone histology and the final patient was not subclassifiable on the basis of the submitted material. The baseline characteristics of all 29 eligible patients are summarized in Table 1. Of note, 13 patients had not received any prior chemotherapy treatment.
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treatment delivery and tumor response
A total of 127 cycles of treatment were given with a median of four cycles per patient (range 1–9). Eleven patients received at least six cycles of treatment but only 55% of all patients received 90% or more of the planned dose intensity of 1.7 mg/m2 per week (calculated by 4 x 1.3 mg/m2 for 3 weeks) because of a variety of adverse events.
Twenty-eight of the 29 eligible patients were assessable for response: one patient was not assessable because CT scanning was not repeated. There were no confirmed CRs; one patient with initial disease involving lymph nodes and marrow had a CR by imaging and normalization of blood counts, but declined to undergo the bone marrow biopsy required to confirm marrow remission, and consequently was categorized as CRu. As shown in Table 2, 12 other patients achieved a PR for a total response rate of 46.4% (95% confidence interval = 27.5% to 66.1%). The median response duration was 10 months (range 2.1–25.1 months). The response rate was 46.2% (six of 13 patients) in previously untreated patients and 46.7% (seven of 15) in those previously treated. Twelve other patients had SD, two with tumor shrinkage of 41% and 46%, which did not quite meet the PR criteria. The overall duration of SD in these 12 patients was 7.8 months (range 1.2–26.1 months). The median time to progression in all patients was 12.5 months (see Figure 1).
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The median time to response was 1.3 months (5.6 weeks); eight of the 13 responses were observed after two cycles of therapy and an additional five occurred after four cycles. The majority of responders had disease in nodes, marrow or spleen. Few patients had extralymphatic sites of disease: one patient with lung and adrenal involvement also had a PR. Patients with kidney and liver involvement both progressed on therapy. Five of seven patients with nodular histology had a response to therapy and seven of 17 with diffuse histology responded. Neither of the two patients with blastoid features responded to therapy. Ten responding patients discontinued therapy due to toxicity while their response was ongoing; nine due to neuropathic complications.
safety
Five SAEs, including two deaths, were reported in the first 12 patients enrolled on study, all having a combination of fluid retention and edema. Although in the first three cases it appeared that lymphoma and not the study drug was the primary cause of these events, reports of the fourth and fifth SAEs suggested that a causal role for bortezomib could not be excluded. One patient was diagnosed with congestive heart failure and another, who died, had pulmonary congestion diagnosed on post-mortem examination. No common feature could be found in these five patients except that all had edema or effusions at baseline. Trial accrual was suspended in April 2003 to investigate these events and the protocol subsequently amended to exclude patients with preexisting edema, dyspnea 
grade 2, ascites and pleural and pericardial effusions and to monitor patients more intensely for fluid accumulation, cardiac function and renal protein loss. The study was reopened to accrual in September 2003 and no further SAEs were reported following this protocol amendment.
As shown in Table 3, the most common treatment-related non-hematologic adverse event was fatigue (72%), followed by diarrhea (48%), nausea (38%), anorexia (35%), constipation (31%) and rash (28%). There was no relationship between the development of rash and the response to therapy. Sensory neuropathy (48%), neuropathic pain (21%) and myalgia (38%) occurred frequently and were major reasons for dose modifications or for discontinuation of treatment. Indeed, nine responding patients discontinued therapy after two to seven cycles because of myalgia, neuropathic pain or neurosensory toxicity. The most frequent hematologic toxicity was thrombocytopenia (22 of 29 patients)—grade 3 in seven patients, grade 2 in four patients and grade 1 in eleven patients. Twenty-four patients had anemia (grade 3 = one, grade 2 = six, grade 1 = 17) and 12 patients had neutropenia (grade 3 = two, grade 1 = 10). Biochemical changes were minimal; in patients with normal baseline chemistries, all elevations seen were grade 1.
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In addition to the five SAEs involving fluid retention (see above), two other SAEs were documented in patients after discontinuing bortezomib. One responding patient discontinued bortezomib due to grade 3 myalgia and later experienced increasing muscle weakness requiring hospitalization. Another patient experienced memory loss, confusion and speech impairment 3 months after completing bortezomib; magnetic resonance imaging scanning revealed increased left frontal and temporal lobe white matter signaling which did not follow a typical vascular pattern and thus was suspicious for inflammatory or neoplastic etiology. The investigator concluded that, in the absence of another diagnosis, these changes were probably related to bortezomib. The patient died of progressive lymphoma 2 months later and no post-mortem examination was undertaken so no further details on the CNS findings were available.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Our results indicate that single-agent bortezomib, at a dose of 1.3 mg/m2 given twice weekly every 21 days is active when treating patients with mantle cell lymphoma. We observed an overall response rate of 46% with similar rates seen in newly diagnosed (six of 13; 46%) and previously treated (seven of 15; 47%) patients. The population we treated appeared to be typical for this disease with a predominance of males (72%), presence of advanced-stage disease (100%) and a median age of 67 years.
These results are consistent with two other phase II studies [17, 18] evaluating bortezomib in patients with mantle cell lymphoma, with these trials both testing higher drug doses of 1.5 mg/m2 given twice weekly every 21 days. Goy [17] reported a response rate of 41% in 29 assessable previously treated patients and O'Connor [18] observed a 50% response rate in 10 assessable patients. Table 4 provides a comparison of the results of our study with those of Goy and O'Connor. We observed a 10-month median duration of response, which was surprisingly durable given the nature of single-agent treatment. Goy reported similar findings with 80% of responses still maintained at 6 months. In all three studies, median time to response was similar (4–6 weeks).
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The most frequent treatment-related toxic effects we observed were also similar to those observed in the two other phase II studies. The most common non-hematologic adverse events were fatigue, which was noted in 72% of the patients, including 28% with grade 3–4 toxicity, and sensory neuropathy, which was seen in 48% of the patients. The trials of Goy and O'Connor tested bortezomib in multiple histologic groups of lymphoma patients and reported toxic effects for these combined groups. O'Connor observed fatigue in 50% of the patients and Goy reported grade 3–4 fatigue in 15%; sensory neuropathy was seen in 73% of the patients in the O'Connor study. Among the hematologic effects, thrombocytopenia was most common with toxicity of at least grade 3 seen in 24% of our patients, similar to the observation of 27% and 49% in the O'Connor and Goy studies.
These toxic effects limited the duration of bortezomib therapy in our study. We were able to administer a median of four treatment cycles and only 55% of the patients received 90% or more of the projected dose intensity. Similar findings were reported by Goy; in that trial, the median number of treatment cycles administered was 2.1, 18% of the patients required dose attenuations and 22% discontinued therapy because of adverse reactions. Similarly, O'Connor reported that the median number of treatment cycles received was four and that 59% of the patients missed at least one dose of therapy with the median number of missed doses being four.
Our trial is the first to report a potential association between bortezomib and susceptibility to fluid retention. While we are unable to exclude other associations, this syndrome appeared to be associated with the presence of preexisting disease-related edema or effusions. The contributions of preexisting disease, drug toxicity, tumor lysis or other cytokine activity to this syndrome are uncertain. We did not observe this complication after instituting a protocol amendment to exclude patients with grade 2 edema, ascites and/or pleural or pericardial effusions.
In summary, we conclude that bortezomib as an active and sufficiently well tolerated agent to warrant further testing in patients with mantle cell lymphoma. Given the consistency of response rates between the three studies and the similarities in treatment toxicity and associated dosing implications, we also conclude that this testing should emphasize the development of new combination regimens rather than alterations of the single-agent administration.
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Acknowledgements |
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We would like to thank the following investigators who, in addition to the authors, contributed patients to this study: Joseph Connors and Paul Hoskins (BC Cancer Agency, Vancouver, British Columbia), John H. Matthews (Kingston Regional Cancer Centre, Kingston, Ontario), A. Robert Turner and Scott North (Cross Cancer Institute, Edmonton, Alberta), Jeannine Kassis (Hopital Maisonneuve-Rosemont, Montréal, Quebec), Reinhard Lohmann (London Regional Cancer Centre, London, Ontario) and Brent Schacter (Cancer Care Manitoba, Winnipeg, Manitoba). This study was supported by a research grant from the National Cancer Institute of Canada with funds received from the Canadian Cancer Society.
Received for publication May 3, 2006. Revision received July 12, 2006. Accepted for publication July 26, 2006.
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