Journal of the National Cancer Institute Advance Access originally published online on July 29, 2008
JNCI Journal of the National Cancer Institute 2008 100(15):E1; doi:10.1093/jnci/djn212
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Published by Oxford University Press 2008.
ONLINE COMMENTARY |
Eighth Biannual Report of the Cochrane Haematological Malignancies Group—Focus on Chronic Lymphatic Leukemia
Affiliations of authors: Cochrane Haematological Malignancies Group, First Department of Internal Medicine 1 (CH, IM, NS) and First Department of Internal Medicine 1, University Hospital of Cologne (AE), Cologne, Germany
Correspondence to: Christine Herbst, MD,MPH, Cochrane Haematological Malignancies Group, Department of Internal Medicine 1, University Hospital of Cologne, Kerpener Strasse 62, D-50924 Cologne, Germany (e-mail: christine.herbst{at}uk-koeln.de).
 |
Introduction |
|---|
The Cochrane Haematological Malignancies Group, based at Cologne, Germany, searches continuously and systematically for clinical trials in the field of hemato-oncology. Randomized controlled trials (RCTs) are identified through electronic search of Medline (OVID gateway) using a broad search filter that covers all topics in hemato-oncology combined with a highly sensitive search filter for randomized studies (Cochrane handbook for systematic reviews of interventions 4.2.5; Appendix 5b.2—phase 1 and phase 2; The Cochrane Collaboration 2006 [updated September 2006] http://www.cochrane.org/resources/handbook/Handbook4.2.6Sep2006.pdf). The search presented here covers publications from April 2007 to December 2007.
In these 9 months, 79 controlled clinical trials (RCTs and nonrandomized clinical trials) were published on therapeutic interventions in several hematologic malignancies (eg, Hodgkin and non-Hodgkin lymphoma, multiple myeloma, and acute and chronic leukemia).
In our present summary of key features of recent RCTs, we focus on chronic lymphatic leukemia. Four recently published trials in patients with chronic lymphocytic leukemia (CLL) are presented in detail: three examine different therapeutic options for first-line therapy for CLL and one addresses the role of oblimersen sodium (Bcl-2 antisense) as an addition to cyclophosphamide and fludarabine. In lesser detail, we present the results of three other interesting trials published during the 9-month period.
After a short overview of the clinical relevance and the selection of patients for these trials, we discuss important methodologic aspects of each trial, eg, randomization, loss to follow-up, dropout rate, and statistical analysis. We also discuss the results of the primary efficacy endpoints and the methods used to report health-related quality of life.
The main objective of this summary report is to provide the knowledge in a way that busy practitioners can easily interpret it.
|
Published Trials in Patients With CLL |
|---|
CLL is a chronic disease of the B-cell lineage that is characterized by an accumulation of ineffective lymphocytes. Because early treatment is not associated with increased length of survival, treatment is reserved for patients with clinical symptoms or rapidly progressing disease. CLL is staged according to the Binet criteria or Rai's criteria, both of which are based on the number of lymphatic sites or organs (liver, spleen) affected as well as the hemoglobin and thrombocyte levels in the blood (1). However, there is a wide range of survival times even within these clinical stages. A number of prognostic markers have been proposed, including cytogenetic markers [eg, the deletion at (11)(q22.3) or (17)(p13.1) as markers of disease progression (2)]. In clinical trials, some of these markers have been used to test the efficacy of earlier or more aggressive treatment regimens (3).
Standard treatment for CLL includes chemotherapy with chlorambucil or the purine antagonist fludarabine. A systematic review compared purine analogues, such as fludarabine, with chemotherapy and showed increased response rates and longer progression-free survival with the purine analogues. However, the improvement in overall survival was not statistically significant (4). Recently, it has been proposed to add cyclophosphamide to fludarabine (3), and two such trials are discussed here. One is a three-arm study also including chlorambucil. We also present two other trials with alternative therapeutic options, the monoclonal antibody alemtuzumab for first-line CLL and the Bcl-2 antisense oblimersen for relapsed CLL.
First-Line Therapy of CLL: Chlorambucil, Fludarabine, or Fludarabine Plus Cyclophosphamide
Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomized controlled trial. Lancet. 2007;370(9583):230–239. (5)
Clinical background.
Standard treatment for CLL is chlorambucil, fludarabine, or fludarabine plus cyclophosphamide (6,7). The addition of cyclophosphamide to fludarabine is thought to improve the response to treatment and thus progression-free and overall survival (8,9). Because no treatment has yet been shown to improve overall survival, quality of life of patients during and after treatment is important.
Contribution.
This prospective trial, conducted in eight countries, recruited 777 untreated patients (aged 35–86 years) with CLL in Binet stages B, C, or A with rapidly progressive disease. Patients were randomly assigned to one of the three treatment arms: up to 12 cycles of chlorambucil (150 mg/m2 orally for 7 days), six cycles of single-agent fludarabine (25 mg intravenously or 50 mg orally for 5 days), or six cycles of fludarabine (25 mg intravenously or 50 mg orally for 5 days) plus cyclophosphamide (150 mg/m2 intravenously for 3 days). The primary endpoint was overall survival. Secondary endpoints included progression-free survival, adverse effects, and health-related quality of life using the European Organization for Research and Treatment of Cancer (EORTC) health-related quality-of-life questionnaire QLQ-C30 (10).
Implication for practice.
The addition of cyclophosphamide to fludarabine resulted in increased progression-free survival (5-year progression-free survival: fludarabine plus cyclophosphamide [36%], fludarabine alone [10%], and chlorambucil [10%], P < .01 for fludarabine plus cyclophosphamide compared with fludarabine alone and compared with chlorambucil). Although the Kaplan–Meier curves for progression-free survival showed a visible difference between the groups at 2 years, this increase did not translate into an increase of overall survival at 5 years. In contrast, there was a trend toward increased survival in the chlorambucil group (59% survived in the chlorabucil group, 52% in the fludarabine group, and 54% in the fludarabine plus cyclophosphamide group; the differences are not statistically significant). In contrast to the meta-analysis by Steurer et al. (4), fludarabine alone was similar to chlorambucil with respect to progression-free survival. The number of serious adverse events was higher in the groups receiving fludarabine plus cyclophosphamide or fludarabine alone. In addition, quality-of-life scores were higher in patients who responded to treatment than those who did not. However, there was no statistically significant difference in the quality-of-life scores between the groups. The validity of the trial is hampered by the recruitment of approximately 250 patients more than the number determined through the sample size calculation, even though the authors report that this was done without the knowledge of the results of the trial. Based on the results of this trial, there is no evidence for the superiority of one of the regimens examined. The choice of treatment may depend on patient or physician preferences, also with regard to the incidence of adverse events.
Most interesting feature.
Three-arm study comparing two older treatments (chlorambucil and fludarabine) with one newer one (fludarabine plus cyclophosphamide).
Key study features are as follows.
|
|
Quality of Life Using Fludarabine Alone or Fludarabine Plus Cyclophosphamide as First-Line Therapy of CLL |
|---|
Eichhorst B, Busch R, Obwandner T, et al. Health-related quality of life in younger patients with chronic lymphocytic leukemia treated with fludarabine plus cyclophosphamide or fludarabine alone for first-line therapy: a study by the German CLL Study Group. J Clin Oncol. 2007;25:1114–1120. (11)
Further information retrieved from:
Eichhorst B, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood. 2006;107:885–891. (12)
|
Contribution. |
|---|
This prospective trial, conducted in two countries, recruited 375 untreated patients (aged 42–65 years) with CLL in Binet stage C, B with symptoms, or A with severe B symptoms. The diagnosis of CLL was confirmed through a central histologic review and patients with severe organ dysfunction or previous neoplasms were excluded from the study. Patients were randomly assigned to up to six 28-day cycles of either single-agent fludarabine (25 mg intravenously for 5 days) or fludarabine (30 mg intravenously for 3 days) with cyclophosphamide (250 mg/m2 intravenously for 3 days). The primary outcome of the trial was progression-free survival, ie, the time from randomization to tumor progression or death. Secondary outcomes include overall survival, response to second-line treatment, and health-related quality of life, presented in detail in the 2007 publication.
The median progression-free survival was more than 2 years longer in the group receiving the combination therapy; the median was 48 compared with 20 months with fludarabine alone. However, the length of overall survival did not differ between the two groups, with 80% surviving 3 years in both groups. The health-related quality of life did not differ between the treatment groups in the two study years, but treatment resulted in a small improvement of health-related quality of life after 1 year in both groups. The improvement in progression-free survival leads the authors to conclude that fludarabine plus cyclophosphamide should be considered the standard first-line treatment in patients with CLL. Due to the chronic nature of the disease, longer follow-up times than the 3 years reported here are needed to assess the potential effects of the increased progression-free survival on overall survival or health-related quality of life.
|
Most interesting feature. |
|---|
 TopIntroductionPublished trials in patients...Quality of life using...Contribution. Most interesting feature. First-line therapy for cll:...Clinical background.Contribution.Implications for practice.Most interesting feature.Treatment of relapsed cllClinical background.Contribution.Implications for practice.Most interesting feature.Methodological issues: health...Other interesting trialsThe cochrane libraryReferences |
|---|
Detailed analysis of health-related quality of life.
Key study features are as follows.
|
|
First-Line Therapy for CLL: Alemtuzumab Compared With Chlorambucil |
|---|
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(35):5616–5623. (13)
|
Clinical background. |
|---|
Alemtuzumab is a recombinant monocloncal antibody directed against CD 52, a cell surface protein that is expressed on normal and leukemic B and T lymphocytes but not on hematopoetic stem cells (14). Until now, it has been used in patients with relapsed or refractory CLL after fludarabine and alkylator therapy. In addition, alemtuzumab has eradicated minimal residual disease in some patients with CLL (15–17). The role of alemtuzumab as a first-line therapy of CLL is unclear. Due to the activity against normal lymphocytes, patients receiving alemtuzumab are at increased risk for infections.
|
Contribution. |
|---|
This 44-center prospective trial recruited 297 patients (aged 35–86 years) with previously untreated flow cytometry confirmed CLL in Rai stages I through IV with progression according to the National Cancer Institute (NCI) Working Group guidelines. Patients with severe organ dysfunction, previous neoplasms, previous stem cell transplantations, HIV, or active infections were excluded from the trial. Patients were randomly assigned to alemtuzumab (30 mg three times a week after dose escalation, maximum of 12 weeks) or chlorambucil (40 mg/m2 for 28 days for up to 12 cycles). Supportive care consisted of diphenhydramine and acetaminophen or paracetamol as premedication for alemtuzumab as well as prophylactic antibiotics in the alemtuzumab arm. Patients in the chlorambucil arm received allopurinol during the first four cycles. The primary outcome was progression-free survival, as defined by the NCI Working Group guidelines.
|
Implications for practice. |
|---|
Progression-free survival was increased in the group receiving alemtuzumab with a median survival of 14.6 months compared with 11.7 months with chlorambucil. Overall survival rate was similar with 84% at 24.6 months in both groups. There was an increased number of adverse events in the alemtuzumab arm (25.6% of patients vs 6.8% of patients receiving chlorambucil). This is mainly due to an increase in cytomegalovirus (CMV) events. Further trials comparing alemtuzumab to fludarabine plus cyclophosphamide or even fludarabine alone or chlorambucil will be required to define the role of alemtuzumab in the treatment of CLL, because no survival advantage was observed and there was a high number of CMV events.
|
Most interesting feature. |
|---|
|
TopIntroductionPublished trials in patients...Quality of life using...Contribution.Most interesting feature.First-line therapy for cll:...Clinical background.Contribution.Implications for practice.Most interesting feature.Treatment of relapsed cllClinical background.Contribution.Implications for practice.Most interesting feature.Methodological issues: health...Other interesting trialsThe cochrane libraryReferences |
|---|
Description of CMV events.
Key study features are as follows.
|
|
Treatment of Relapsed CLL |
|---|
O'Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia.J Clin Oncol. 2007;25(9):1114–1120. (18)
|
Clinical background. |
|---|
Treatment options for relapsed or refractory CLL depend on the first treatment the patient received. In particular, patients who become refractory to fludarabine have a poor prognosis (7). Therapy targeting specific cytogenetic mutations may be an option for these patients. Oblimersen is an antisense oligonucleotide that reduces levels of both Bcl-2 mRNA and Bcl-2 protein. Increased expression of the antiapoptotic regulatory Bcl-2 protein plays a critical role in CLL (19): it is expressed in almost all patients but in varying amounts. In CLL cells, oblimersen potentiates the cytotoxic activity of commonly used CLL agents such as fludarabine, rituximab, and alemtuzumab (19). Addition of oblimersen may thus improve response rates in patients with CLL when used in combination with the above-mentioned agents.
|
Contribution. |
|---|
This single-center prospective trial recruited 241 patients (aged 42–65 years) with relapsed CLL or no response to prior chemotherapy with fludarabine in intermediate or high risk stage according to the Rai criteria. Patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower, adequate organ function, and platelet count of at least 50 000/mm3 without hematopoietic growth factor or transfusion support. Patients were randomly assigned to up to six 28-day cycles of either fludarabine (25 mg intravenously for 3 days) with cyclophosphamide (250 mg/m2 intravenously for 3 days) or fludarabine (25 mg intravenously on days 5, 6, and 7) and cyclophosphamide (250 mg/m2 intravenously days 5, 6, and 7) and oblimersen 3 mg/kg/d (7 days continous infusion). Primary endpoint was tumor response rate, that is, rate of complete remission (CR) or nodular partial remission (nPR; ie, patients in clinically CR but in whom bone marrow nodules can be identified histologically).
|
Implications for practice. |
|---|
Twenty patients (17%) in the chemotherapy plus oblimersen group achieved CR/nPR compared with eight (7%) in the chemotherapy-only group (CR 9% vs 3%). Overall survival was similar, with a median survival of 33.8 months in the oblimersen group compared with 32.9 months in the chemotherapy-alone group (no HR calculated or CIs presented). Further large trials are required to determine the effect of the addition of oblimersen to fludarabine plus cyclophosphamide on overall survival.
|
Most interesting feature. |
|---|
|
TopIntroductionPublished trials in patients...Quality of life using...Contribution.Most interesting feature.First-line therapy for cll:...Clinical background.Contribution.Implications for practice.Most interesting feature.Treatment of relapsed cllClinical background.Contribution.Implications for practice.Most interesting feature.Methodological issues: health...Other interesting trialsThe cochrane libraryReferences |
|---|
Primary outcome response and not overall survival.
Key study features are as follows.
|
|
Methodological Issues: Health-Related Quality of Life |
|---|
The chronic nature of CLL, combined with with the limited effects of different therapies on the length of overall survival, raises the importance of the quality of life of the patients. Three trials reported some quality-of-life measures. Two trials reported these through use of the EORTC health-related quality-of-life questionnaire QLQ-C30 (5,11), and O'Brien (18) presented proxies such as the resolution of B symptoms (night sweats and fever) and the improvement in performance status. The EORTC QLQ-C30 questionnaire takes on average 11–13 minutes to fill out and has been validated for a number of European countries (10,20). It includes questions relating to physical fitness, degree of pain, and perceived quality of life. It has been recommended for routine use in oncological practices (21).
A key difficulty in interpreting the results of a health-related quality-of-life analysis is determining which difference in score is a meaningful clinical difference (22). Ideally, such a difference should be defined before the trial, and the proportion of improvements or deteriorations be reported; this was not done in either of the two trials reporting quality of life using a validated questionnaire. Another difficulty encountered in both trials is that patients who responded to therapy were more likely to fill out the questionnaire, making it more difficult to assess differences attributable to a difference in tumor response rate or progression-free survival. Only the trial by Eichorst (11) reported full information about the quality-of-life analysis including the responses to individual questions.
|
Other Interesting Trials |
|---|
Dimopoulos M, Spencer; Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:2123–2132. (23)
This multicenter trial, which was supported by Celgene, examined the effect of adding the thalidomide analogue lenalidomide to high-dose dexamethasone in patients with relapsed or refractory multiple myeloma. Patients who did not respond to previous treatment with high-dose dexamethasone were excluded; 30% of patients included had received therapy with thalidomide in the past. Both progression-free and overall survival were increased in the combination group. Median progression-free survival was 11.3 months, compared with 4.3 months with dexamethasone alone; median overall survival was not reached at the time of analysis (median follow-up of 16.4 months) for the lenalidomide combination group and was 20.6 months in the dexamethasone alone group. The incidence of severe adverse events was increased in the group receiving lenalidomide, primarily through the increased neutropenia and thromboembolic events.
Herold M, Haas A, Srock S, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol. 2007;25(15):1986–1992. (24)
This multicenter trial examined the effect of adding rituximab to eight cycles of mitoxantrone, chorambucil, and prednisolone for patients with low-grade advanced follicular lymphoma. In the group receiving rituximab, the overall and complete response rates were 92% and 50%, respectively, compared with 75% and 25% in the group receiving chemotherapy alone. The difference was also translated into an increase in 4-year overall survival. Eighty-seven percent of patients who received rituximab survived for 4 years compared with 74% of the chemotherapy-alone group. There were more adverse events in the group receiving rituximab with 97% of patients reporting an adverse event compaerd to 86% in the chemotherapy-alone group. The main increase was in the increase of grade 3 and 4 neutropenia without an increase in the incidence of infections. Adding rituximab to chemotherapy with mitoxantrone, chorambucil, and prednisolone can be recommended.
Engert A, Franklin J, Eich HT, et al. Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin lymphoma: final results of the GHSG HD7 trial. J Clin Oncol. 2007; 25(23):3495–34502. (25)
This multicenter trial included 650 patients for the evaluation of whether combined mortality treatment with two cycles of doxorubicin, bleomycin, vinbalstine, and dacarbazine (ABVD) followed by extended field radiotherapy is superior to extended field radiotherapy for patients with early favorable Hodgkin lymphoma. Patients with histologically proven Hodgkin lymphoma in clinical stage I and II without unfavorable risk factors such as a large mediastinal mass, extranodal disease, massive splenic involvement, and high erythrocyte sedimentation rate were excluded. Although response rates and overall survival were similar in the group receiving ABVD compared with the one with radiotherapy alone, the freedom from treatment failure at a median observation time of 87 months was statistically significantly increased through the addition of ABVD chemotherapy to 88% (67% radiotherapy alone). ABVD therapy before radiotherapy did not increase the toxicity of radiotherapy.
|
The Cochrane Library |
|---|
In the new issue of the Cochrane Library (Issue I 2008 published: 23 January 2008; see http://www.thecochranelibrary.com/), one new review and a major update for a protocol were published.
New Reviews
The new review "High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive Non-Hodgkin Lymphoma (NHL) in adults" (by Greb A, Bohlius J, Schiefer D, Schwarzer G, Schulz H, Engert A) analyzed whether high-dose chemotherapy with autologous stem cell transplantation as part of first-line treatment improves survival in patients with aggressive non-Hodgkin lymphoma. Fifteen RCTs including 3079 patients were eligible for this meta-analysis. Overall treatment-related mortality was 6.0% in the HDT group and not significantly different compared with conventional chemotherapy (OR 1.33, 95% CI 0.91 to 1.93, P = .14). Thirteen studies including 2018 patients showed statistically significantly higher CR rates in the group receiving HDT (OR 1.32, 95% CI 1.09 to 1.59, P = .004). However, HDT did not have an effect on overall survival, when compared with conventional chemotherapy. The pooled HR was 1.04 (95% CI 0.91 to 1.18, P = .58). Event-free survival also showed no significant difference between HDT and CT (HR 0.93, 95% CI 0.81 to 1.07, P = .31). The authors concluded that despite higher CR rates, there is no benefit for high-dose chemotherapy with stem cell transplantation as a first-line treatment in patients with aggressive non-Hodgkin lymphoma.
New Protocols
There was one updated protocol approved through the editorial process:
"First-line double high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma (by Naumann F, Schnell R, Herbst C, Brillant C, Schulz H, Greb A, Bohlius JB, Djulbegovic B, Wheatley K, Engert A).
|
REFERENCES |
|---|
1. Chiorazzi N, Rai KR, Ferrarini M. Chronic lymphocytic leukemia. N Engl J Med (2005) 352(8):804–815.
2. Byrd JC, Gribben JG, Peterson BL, et al. Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol (2006) 24(3):437–443.
3. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 guidelines. Blood (2008) 111(12):5446–5456.
4. Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R. Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev. (2006) 3. CD004270.
5. Catovsky D, Richards S, Matutes E, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet (2007) 370(9583):230–239.[CrossRef][Web of Science][Medline]
6. Oscier D, Fegan C, Hillmen P, et al. Guidelines on the diagnosis and management of chronic lymphocytic leukaemia. Br J Haematol (2004) 125(3):294–317.[CrossRef][Web of Science][Medline]
7. Chemotherapeutic options in chronic lymphocytic leukemiaa meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst (1999) 91(10):861–868.
8. O'Brien SM, Kantarjian HM, Cortes J, et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol (2001) 19(5):1414–1420.
9. Byrd JC, Lin TS, Grever MR. Treatment of relapsed chronic lymphocytic leukemia: old and new therapies. Semin Oncol (2006) 33(2):210–219.[CrossRef][Web of Science][Medline]
10. Osoba D, Aaronson N, Zee B, Sprangers M, te VA. Modification of the EORTC QLQ-C30 (version 2.0) based on content validity and reliability testing in large samples of patients with cancer. The Study Group on Quality of Life of the EORTC and the Symptom Control and Quality of Life Committees of the NCI of Canada Clinical Trials Group. Qual Life Res. (1997) 6(2):103–108.[Web of Science][Medline]
11. Eichhorst BF, Busch R, Obwandner T, et al. Health-related quality of life in younger patients with chronic lymphocytic leukemia treated with fludarabine plus cyclophosphamide or fludarabine alone for first-line therapy: a study by the German CLL Study Group. J Clin Oncol (2007) 25(13):1722–1731.
12. Eichhorst BF, Busch R, Hopfinger G, et al. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood (2006) 107(3):885–891.
13. Hillmen P, Skotnicki AB, Robak T, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia [see comment]. J Clin Oncol (2007) 25(35):5616–5623.
14. Lozanski G, Heerema NA, Flinn IW, et al. Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood (2004) 103(9):3278–3281.
15. Moreton P, Kennedy B, Lucas G, et al. Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol (2005) 23(13):2971–2979.
16. Lundin J, Kimby E, Bjorkholm M, et al. Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood (2002) 100(3):768–773.
17. O'Brien SM, Kantarjian HM, Thomas DA, et al. Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia. Cancer (2003) 98(12):2657–2663.[CrossRef][Web of Science][Medline]
18. O'Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol (2007) 25(9):1114–1120.
19. Chanan-Khan A. Bcl-2 antisense therapy in B-cell malignancies. Blood Rev. (2005) 19(4):213–221.[CrossRef][Web of Science][Medline]
20. Groenvold M, Klee MC, Sprangers MA, Aaronson NK. Validation of the EORTC QLQ-C30 quality of life questionnaire through combined qualitative and quantitative assessment of patient-observer agreement. J Clin Epidemiol (1997) 50(4):441–450.[CrossRef][Web of Science][Medline]
21. Coates A, Porzsolt F, Osoba D. Quality of life in oncology practice: prognostic value of EORTC QLQ-C30 scores in patients with advanced malignancy. Eur J Cancer (1997) 33(7):1025–1030.[CrossRef][Web of Science][Medline]
22. Efficace F, Osoba D, Gotay C, Sprangers M, Coens C, Bottomley A. Has the quality of health-related quality of life reporting in cancer clinical trials improved over time? Towards bridging the gap with clinical decision making. Ann Oncol (2007) 18(4):775–781.
23. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med (2007) 357(21):2123–2132.
24. Herold M, Haas A, Srock S, et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol (2007) 25(15):1986–1992.
25. Engert A, Franklin J, Eich HT, et al. Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial. J Clin Oncol (2007) 25(23):3495–3502.
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||