help button home button The Oncologist http://theoncologist.alphamedpress.org/subscriptions/etoc.dtl
HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
The Oncologist, Vol. 13, No. 2, 167-174, February 2008; doi:10.1634/theoncologist.2007-0218
© 2008 AlphaMed Press

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow CME: Take the course for this article:
 FDA Drug Approval Summary: Alemtuzumab as Single-Agent Treatment for B-Cell...
Right arrow eLetters: Submit a response to this article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Demko, S.
Right arrow Articles by Pazdur, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Demko, S.
Right arrow Articles by Pazdur, R.

Regulatory Issues: FDA

FDA Drug Approval Summary: Alemtuzumab as Single-Agent Treatment for B-Cell Chronic Lymphocytic Leukemia

Suzanne Demko, Jeffrey Summers, Patricia Keegan, Richard Pazdur

Division of Biologic Oncology Products, Office of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, Maryland, USA

Key Words. Chronic lymphocytic leukemia • Progressive disease • First-line therapy • Alemtuzumab • Chlorambucil

Correspondence: Suzanne Demko, P.A.-C., U.S. Food and Drug Administration, 10903 New Hampshire Avenue, WO#22 Room 2307, Mail Stop 2343, Silver Spring, Maryland 20993, USA. Telephone: 301-796-2108; Fax: 301-796-9849; e-mail: suzanne.demko{at}fda.hhs.gov

Received November 2, 2007; accepted for publication January 8, 2008.

Disclosure: No potential conflicts of interest were reported by the authors, planners, reviewers, or staff managers of this article.


   LEARNING OBJECTIVES
Top
 Footnotes
 Learning Objectives
Abstract
 Introduction
 Patients and Methods
 Results
 Safety
 Discussion
 Acknowledgments
 References
 
After completing this course, the reader will be able to:

  1. Discuss the results of the CAM 307 randomized trial of alemtuzumab in patients with B-cell chronic lymphocytic leukemia.
  2. Describe the pretreatment and prophylactic medications recommended for patients treated with alemtuzumab.
  3. Identify the most common toxicities seen with alemtuzumab treatment.

Access and take the CME test online and receive 1 AMA PRA Category 1 CreditTM at CME.TheOncologist.com


   ABSTRACT
Top
 Footnotes
 Learning Objectives
 Abstract
Introduction
 Patients and Methods
 Results
 Safety
 Discussion
 Acknowledgments
 References
 
On September 19, 2007, the U.S. Food and Drug Administration granted regular approval and expanded labeling for alemtuzumab (Campath®; Genzyme Corporation, Cambridge, MA) as single-agent treatment for B-cell chronic lymphocytic leukemia (B-CLL). Alemtuzumab was initially approved in 2001 under accelerated approval regulations. Conversion to regular approval was based on a single study submitted to verify clinical benefit. Efficacy and safety were demonstrated in an open-label, international, multicenter, randomized trial of 297 patients with previously untreated, Rai stage I–IV B-CLL experiencing progression of their disease. Patients were randomized to either alemtuzumab, 30 mg i.v. over 2 hours three times per week on alternate days for a maximum of 12 weeks, or chlorambucil, 40 mg/m2 orally every 28 days for a maximum of 12 months. The progression-free survival time, the primary study endpoint, was significantly longer in the alemtuzumab arm than in the chlorambucil arm. Both the overall and complete response rates were also significantly higher in the alemtuzumab arm. No differences in survival were observed. There were no new safety signals identified in patients receiving alemtuzumab. The most serious, and sometimes fatal, toxicities of alemtuzumab are cytopenias, infusion reactions, and infections.


   INTRODUCTION
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
Patients and Methods
 Results
 Safety
 Discussion
 Acknowledgments
 References
 
Alemtuzumab (Campath®; Genzyme Corporation, Cambridge, MA) is a recombinant DNA-derived humanized IgG1 kappa monoclonal antibody specific for the cell surface glycoprotein CD52 expressed on normal and malignant human peripheral blood B and T lymphocytes as well as natural killer cells, monocytes, macrophages, and other tissues. The mechanism of action is not completely understood, but involves a number of effects, including complement-mediated cell lysis, antibody-dependent cellular toxicity, and the induction of apoptosis. Because of its immunosuppressive properties, alemtuzumab was investigated initially for the treatment of autoimmune diseases and in transplant [1, 2]. Clinical activity was then demonstrated in a number of malignancies, including chronic lymphocytic leukemia (CLL) and T-cell prolymphocytic leukemia [3–5], which led to further investigation in these settings.

The U.S. Food and Drug Administration (FDA) granted accelerated approval for alemtuzumab on May 7, 2001, for the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL) who had been treated with alkylating agents and failed fludarabine therapy based on evidence of durable objective response rates in the range of 21%–33% across three single-arm studies. U.S. regulatory approval was contingent upon completion of a postmarketing commitment to confirm clinical benefit in the CAM 307 trial. CAM 307 was an open-label, international, multicenter, randomized trial designed to demonstrate a longer progression-free survival (PFS) duration with single-agent alemtuzumab than with single-agent chlorambucil in patients with previously untreated, Rai stage I–IV B-CLL experiencing progression of their disease requiring initiation of antileukemia treatment. The analyses of the primary (PFS) and key secondary endpoints were performed on an intent-to-treat (ITT) population of 297 patients. Conversion from accelerated to regular approval for alemtuzumab and a new labeling claim for the initial treatment of B-CLL on September 19, 2007, were supported by evidence of a significant and clinically meaningful longer PFS time, supported by higher overall and complete response rates.


   PATIENTS AND METHODS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
Results
 Safety
 Discussion
 Acknowledgments
 References
 
The CAM 307 trial was an open-label, randomized (1:1), multicenter trial conducted in Europe and the U.S., comparing the safety and efficacy of single-agent alemtuzumab with those of single-agent chlorambucil in previously untreated patients with B-CLL who required systemic therapy for progressive disease [6]. The intended sample size of 284 patients was chosen to detect a 50% difference in the median PFS time (14 versus 21 months), with 80% power and {alpha} = 0.05 (two-sided). Randomization was stratified with an adaptive randomization method used to achieve balance between the treatment arms for study center, Rai stage group (Rai I–II versus Rai III–IV), age (<65 years versus ≥65 years), World Health Organization (WHO) performance status score (0 or 1 versus 2), gender, and maximum lymph node size (nonpalpable or <5 cm versus ≥5 cm).

The primary efficacy endpoint for the trial was the PFS duration, calculated from the date of randomization to the date of disease progression or relapse as documented by an independent response review panel (IRRP) or the date of death from any cause, whichever occurred earlier. Patients without IRRP-documented disease progression who were alive on the date of last evaluation were censored at the date of last contact. Patients with missing tumor response assessments were considered to have progressed on the date of the inevaluable response determination plus 1 day. The statistical analysis plan specified a single interim analysis of PFS after 95 events and a final analysis of PFS after 70% of the population had progressed or died (190 events). Protocol-specified exploratory analyses of PFS were planned to assess for consistency of treatment effect within the following subgroups: age (<65 years versus ≥65 years), maximum lymph node diameter (nonpalpable or <5 cm versus ≥5 cm), gender, performance status (0 or 1 versus 2), percent marrow involvement, β2-microglobulin, and cytogenetic abnormalities. Additional study endpoints included overall survival, investigator-determined PFS, IRRP-determined overall and complete response rates, duration of response, time to treatment failure, and time to alternative treatment. Complete response (CR) and partial response (PR) were defined using the 1996 National Cancer Institute Working Group (NCIWG) criteria summarized in Table 1.


View this table:
[in this window]
[in a new window]

  		Table 1. 1996 NCIWG response criteria

 
The protocol defined duration of response as the interval between the date of first documented objective response and the date of documented progressive disease or death from any cause as determined by the IRRP. The design of the case report forms, which were reviewed by the IRRP, did not clearly indicate that the intended date of response was the date of initial response. As a result, the IRRP provided the date of best response, and the duration of response analysis was performed using this time point and the censoring rules from the primary PFS analysis. Patients were evaluated for disease status response and survival monthly during treatment and at the completion of treatment or early discontinuation. Response assessments included physical examination, lymph node, liver, and spleen measurements, assessment of disease-related symptoms, and CBC with differential. In addition, at 1, 2, and 3 months after treatment had begun, flow cytometry was performed on peripheral blood and bone marrow aspirate samples, and bone marrow biopsy samples were obtained for histology if indicated (i.e., to confirm a CR at least 2 months after a patient met the NCIWG laboratory and clinical criteria for CR, and to confirm achievement of a CRm (complete response without evidence of residual disease at the molecular level) status only if peripheral blood was negative for B-CLL by flow cytometry). Patients who did not progress by 18 months after their initial dose were evaluated for disease status every 3 months until the time of progression or requirement for alternative therapy. Patients with disease progression were followed every 3 months for survival. Investigators and the IRRP used the NCIWG criteria to assess tumor response to study treatment.

Patients with previously untreated B-CLL exhibiting evidence of progressive disease were eligible to participate in the trial. Other relevant eligibility criteria are summarized in Table 2.


View this table:
[in this window]
[in a new window]

  		Table 2. CAM 307 eligibility criteria

 
The dosing scheme for alemtuzumab included a dose-escalation phase to achieve the recommended dose. The dose-escalation phase consisted of an initial dose of 3 mg as a daily i.v. infusion administered over 2 hours until infusion-related side effects were tolerated followed by 10 mg as a daily 2-hour i.v. infusion until infusion-related side effects were tolerated, with final escalation to the recommended dose. The recommended dose was 30 mg as a 2-hour i.v. infusion administered three times per week on alternate days. The total course of alemtuzumab was administered over a maximum of 12 weeks, which included the dose-escalation period. Patients randomized to the alemtuzumab arm were permitted to receive a second treatment course if a CR or PR, durable for at least 6 months, was achieved with the initial treatment course. Premedication for alemtuzumab treatment, consisting of diphenhydramine and acetaminophen or paracetamol, was given. Meperidine, hydrocortisone (or equivalent), and other supportive measures were permitted as clinically indicated for alemtuzumab infusion reactions. Allopurinol was given prior to the first treatment with alemtuzumab and for 14 days thereafter. Trimethoprim/sulfamethoxazole for Pneumocystis carinii pneumonia prophylaxis (or therapeutic equivalent) and famciclovir (or therapeutic equivalent) for herpes prophylaxis were required for all patients receiving alemtuzumab. Prophylactic antibiotics to prevent recurrence of an infection were allowed at the investigator's discretion.

Dose modifications (delay or discontinuation of alemtuzumab) were required for serious infection, disease progression, Common Toxicity Criteria (CTC) grade ≥3 pulmonary, renal, or hepatic toxicity, a positive qualitative polymerase chain reaction assay for cytomegalovirus (CMV), autoimmune anemia, or autoimmune thrombocytopenia, an absolute neutrophil count ≤0.25 x 109/l, a platelet count ≤50% of the baseline value in patients with a baseline value ≤0.25 x 109/l; if alemtuzumab dosing was held for >4 weeks, treatment was terminated.

Chlorambucil was administered at a dose of 40 mg/m2 orally once every 28 days for a maximum of 12 months. Chlorambucil was interrupted or discontinued for disease progression, CTC grade ≥3 pulmonary, renal, hepatic, or nonhematologic toxicity, serious infection, autoimmune anemia or autoimmune thrombocytopenia, complete remission, and a response plateau. Allopurinol was given prior to the first day of chlorambucil treatment and for 8 days thereafter for the first three treatment cycles.


   RESULTS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
Safety
 Discussion
 Acknowledgments
 References
 
Two hundred ninety-seven patients were enrolled and randomized from December 2001 to July 2004, which constituted the ITT population for analyses of efficacy endpoints. The last patient received drug in May 2005; the data cutoff for efficacy analyses was June 1, 2006. Of these 297 patients, 149 were randomized to alemtuzumab and 148 to chlorambucil. The majority (273/297) were enrolled at sites outside the U.S. There were 294 patients who received the assigned treatment with alemtuzumab (n = 147) or chlorambucil (n = 147) for which adverse drug reaction data were analyzed.

The baseline characteristics for the ITT population, by treatment arm, are shown in Table 3. The treatment arms were balanced for major demographic and prognostic factors. Gender stratification was similar to that seen in B-CLL, where there is a 2:1 male-to-female ratio. Ninety-nine percent of patients were white, and 65% were <65 years of age. The majority of patients enrolled in the study were IRRP-confirmed RAI stage I–II (63%), had a WHO performance status score of 0 or 1 (96%), and had a maximal lymph node diameter of <5 cm (77%).


View this table:
[in this window]
[in a new window]

  		Table 3. Baseline demographics

 
The final analysis of PFS was conducted after 191 PFS events occurred among 297 patients in the ITT population (149 randomized to alemtuzumab and 148 randomized to chlorambucil). There were 11 patients with IRRP-unconfirmed B-CLL Rai stage I–IV who were censored at day 1 (seven in the alemtuzumab arm and four in the chlorambucil arm).

The difference in PFS duration between the alemtuzumab and chlorambucil treatment arms using the log-rank test, stratified by Rai stage (I–II versus III–IV) was highly statistically significant, with a p-value of .0001 and an estimated hazard ratio of 0.58 (95% confidence interval [CI], 0.43–0.77). The median PFS time was 445 days (14.6 months) in the alemtuzumab arm compared with 357 days (11.7 months) in the chlorambucil arm (Table 4). Figure 1 represents the Kaplan-Meier curves for PFS.


View this table:
[in this window]
[in a new window]

  		Table 4. Major efficacy results for the CAM 307 trial

 


Figure 1
View larger version (14K):
[in this window]
[in a new window]

  		Figure 1. CAM 307 Kaplan-Meier curves for progression-free survival (PFS).

Abbreviation: IRRP, independent response review panel.

 
Across all subgroups, there was a consistently longer PFS time favoring the alemtuzumab arm. The effect was not significant in the following subgroups: patients with Rai stage III–IV (n = 98), with a hazard ratio of 0.651 (95% CI, 0.411–1.033), and patients ≥65 years of age (n = 104), with a hazard ratio of 0.68 (95% CI, 0.418–1.107). Because of the limited number of patients, exploratory analyses comparing effects on PFS conducted in the following subgroups were not meaningful: WHO performance status score of 2 (n = 10), lymph node size ≥5 cm (n = 67), and enrollment at U.S. sites (n = 24).

The study demonstrated a significantly higher overall response rate (83% versus 55%; p < .0001, {chi}2 test) for alemtuzumab-treated patients than for those treated with chlorambucil, with an estimated odds ratio for response of 3.99 (95% CI, 2.33–6.84). The study also demonstrated a significantly higher complete response rate for alemtuzumab of 24% versus 2% when compared with chlorambucil (p < .0001, {chi}2 test). The median duration of response for patients treated with alemtuzumab was 492 days (16.4 months), and it was 386 days (12.9 months) for patients treated with chlorambucil. The impact on the resolution of B-symptoms was also evaluated. At study entry, night sweats were common, reported in 43% of patients who received alemtuzumab and 47% who received chlorambucil. After 3 months of treatment, night sweats were reported in 3% of patients treated with alemtuzumab and 13% treated with chlorambucil.

In the analysis of time to alternative treatment, defined as the time from randomization to the date of alternative treatment or death, patients in the alemtuzumab arm experienced a longer time to alternative treatment than patients in the chlorambucil arm; the median time to alternative treatment was 708 days (23.3 months) among patients in the alemtuzumab arm and 447 days (14.7 months) among patients in the chlorambucil arm (p-value < .0001, log-rank test, unadjusted for multiplicity).

An additional secondary endpoint was time to treatment failure, defined as the time from randomization to the date of progression, death from any cause, study discontinuation because of an adverse event, or treatment interruption because of an adverse event resulting in treatment delay over 4 weeks, whichever was earliest. The time to treatment failure was not significantly different between the two treatment arms, with a median time to treatment failure of 299 days (10 months) for alemtuzumab and of 344 days (11.5 months) for chlorambucil.

There was no difference detected in overall survival between treatment arms; there were 24 deaths in each study arm at the time of analysis. However, the study was not powered to detect a difference in overall survival. There were not enough events or long enough follow-up to detect a difference in survival, and there was no plan for continued follow-up of patients in this study.


   SAFETY
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Safety
Discussion
 Acknowledgments
 References
 
The CAM 307 study did not reveal new safety signals for alemtuzumab. The most common as well as the most serious alemtuzumab toxicities were cytopenias, infusion reactions, and infections, especially CMV infection. Safety findings are summarized in Table 5.


View this table:
[in this window]
[in a new window]

  		Table 5. CAM 307 per patient incidence of common toxicities

 
National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 (NCI-CTCAE) grade 3 or 4 cytopenias occurred more frequently in patients receiving alemtuzumab than in those receiving chlorambucil. These included lymphopenia (99% versus 1%), neutropenia (44% versus 26%), and leukopenia (63% versus 1%). Treatment with alemtuzumab also resulted in decreased CD3+CD4+ and CD3+CD8+ counts of <200 cells/µl, and recovery after discontinuation of alemtuzumab was longer, with a median time to CD4 cell partial recovery (>200 CD4+ cells/µl) of 6 months.

The most common adverse reactions of alemtuzumab (NCI-CTC version 2.0 grades 1–4) were infusion reactions, which were experienced by 86% of patients receiving alemtuzumab. The most common signs and symptoms of an infusion reaction were pyrexia (69%), chills (53%), nausea (18%), hypotension (16%), urticaria (16%), headache (14%), dyspnea (14%), and vomiting (11%). Seen less frequently, with incidence rates of ≤10%, were tachycardia, anxiety, pruritis, tremor, and bronchospasm. The occurrence of infusion reactions was greatest during the initial week of treatment and decreased with subsequent doses. All patients were pretreated with antipyretics and antihistamines, and 43% received glucocorticoids as pretreatment.

Infections occurred in 90% of patients treated with alemtuzumab and 65% of patients treated with chlorambucil. CMV infection was reported in 16% of patients treated with alemtuzumab, of these, 5% were serious adverse events. No patients treated with chlorambucil developed CMV infection. CMV viremia was reported in 56% of patients treated with alemtuzumab and 8% treated with chlorambucil. Antiviral treatment was administered in 44% of patients who developed CMV viremia. Serious adverse events were experienced by 11% of patients, all of whom were treated with alemtuzumab.

Anti-human antibodies to alemtuzumab were detected in 8% of patients tested using an enzyme-linked immunosorbent assay. Patients with detectable antibody titers were also weakly positive when analyzed for neutralizing antibodies in 25% of cases.


   DISCUSSION
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Safety
 Discussion
Acknowledgments
 References
 
The design of study CAM 307 was predicated on alemtuzumab's initial accelerated approval. The U.S. FDA's accelerated approval regulations for serious or life-threatening illnesses (21 CFR 601 Subpart E) include a requirement for a postmarketing study to verify clinical benefit. CAM 307 was designed to fulfill this commitment. At the time the study was designed, chlorambucil was approved for the first-line treatment of B-CLL. The currently available therapies for this patient population in the first-line setting have expanded. Clinical practice has evolved to include a more limited first-line use of chlorambucil as treatment for B-CLL in favor of fludarabine as a single agent or in combination with other therapies. As a result, the relevance of the results from the CAM 307 trial are being questioned [7]. It is inevitable that approaches to therapy in the field of oncology will change while clinical trials designed in another era are being completed. While it is agreed that a trial designed in the current practice setting with fludarabine as the comparator would likely be more informative, the choice of chlorambucil as the comparator in this trial was appropriate and fulfilled the regulatory requirement for confirmation of clinical benefit.

Single-agent alemtuzumab provided a statistically significant and clinically meaningful longer PFS time than with chlorambucil in patients with B-CLL who had been previously untreated, had evidence of disease progression, and were in need of treatment. The data from this randomized, open-label, international, multicenter trial demonstrate that alemtuzumab led to an 88 days (2.9 months) longer median PFS time when compared with chlorambucil and a 42% longer time to disease progression or death. The secondary endpoints of overall response rate and complete response rate were supportive of the primary results, with a significantly higher overall response rate (83% vs. 55%) and complete response rate (24% versus 2%) for alemtuzumab-treated patients. Survival data are immature; there was no evidence of any effect on survival.

No new safety signals were identified in this study. The most common and most serious adverse reactions of alemtuzumab identified during this study were severe and life-threatening cytopenias, infusion reactions, and infections, especially CMV; some of these events were fatal. The toxicity profile of alemtuzumab as demonstrated in this study was consistent with the information already contained in the prescribing information. While the risks associated with alemtuzumab treatment can be significant, in a risk–benefit analysis of this agent for B-CLL treatment, the potential benefits mitigate the frequency and severity of the risks.


   ACKNOWLEDGMENTS
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Safety
 Discussion
 Acknowledgments
References
 
The views expressed are the result of independent work and do not necessarily represent the views and findings of the U.S. FDA.


   FOOTNOTES
 
Conception/design: Suzanne Demko

Collection/assembly of data: Suzanne Demko

Data analysis and interpretation: Suzanne Demko, Jeffrey Summers

Manuscript writing: Suzanne Demko

Final approval of manuscript: Richard Pazdur

Preliminary editing: Jeffrey Summers

Final editing, Division approval: Patricia Keegan


   REFERENCES
Top
 Footnotes
 Learning Objectives
 Abstract
 Introduction
 Patients and Methods
 Results
 Safety
 Discussion
 Acknowledgments
 References
 

  1. Isaacs JD, Watts RA, Hazelman BL et al. Humanised monoclonal antibody therapy for rheumatoid arthritis. Lancet 1992;340:748–752.[CrossRef][Medline]
  2. Hale G, Waldmann H. Recent results using CAMPATH-1H antibodies to control GVHD and graft rejection. Bone Marrow Transplant 1996;17:305–308.[Medline]
  3. Osterborg A, Fassas AS, Anagnostopoulos A et al. Humanized CD52 monoclonal antibody Campath-1H as first-line treatment in chronic lymphocytic leukaemia. Br J Haematol 1996;93:151–153.[CrossRef][Medline]
  4. Osterborg A, Dyer MJ, Bunjes D et al. Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia. J Clin Oncol 1997;15:1567–1574.[Abstract]
  5. Pawson R, Dyer MJ, Barge R et al. Treatment of T-cell prolymphocytic leukemia with human CD52 antibody. J Clin Oncol 1997;15:2667–2672.[Abstract/Free Full Text]
  6. Hillmen P, Skotnicki AB, Robak T et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 2007;25:5616–5623.[Abstract/Free Full Text]
  7. Flynn JM, Byrd JC. Have we forgotten the purpose of phase III studies? J Clin Oncol 2007;25:5553–5555.[Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow CME: Take the course for this article:
 FDA Drug Approval Summary: Alemtuzumab as Single-Agent Treatment for B-Cell...
Right arrow eLetters: Submit a response to this article
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article link to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints/Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Demko, S.
Right arrow Articles by Pazdur, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Demko, S.
Right arrow Articles by Pazdur, R.

HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
THE ONCOLOGIST STEM CELLS CME ALPHAMED PRESS JOURNALS
http://theoncologist.alphamedpress.org/misc/eLetters.shtml