© Oxford University Press 2006.
ONLINE COMMENTARY |
Fourth Biannual Report of the Cochrane Haematological Malignancies Group
Affiliations of authors: Cochrane Haematological Malignancies Group, Cologne, Germany (TK, HH, JB, AE); Department of Internal Medicine I, University of Cologne, Cologne, Germany (JB, AE)
Correspondence to: Thilo Kober, PhD, Smiling Press Productions, 16/21 Cossington-Smith Crescent, ACT 2602, Australia (e-mail: tk_smilingpressproductions{at}yahoo.com.au).
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INTRODUCTION |
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 TopNotes Introduction New chmg reviews or...Published trials |
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This fourth biannual report of the Cochrane Haematological Malignancies Group (CHMG) includes another series of interesting new clinical trials and meta-analysis and provides a summary of key features of these recently published papers. Ongoing trials are not considered. The guiding principles for study selection were implication for clinical practice, methodologic aspects, and timeliness. An electronic search of the Medline (OVID) database, combined with our search filter for randomized studies (http://gateway.ut.ovid.com/gw1/ovidweb.cgi), was undertaken in early December 2005. From 119 identified and screened studies, we selected 10 randomized controlled trials for information and discussion, published from early May to the first week of December 2005. Most identified studies published during the second half of 2005 dealt with various aspects of stem cell and bone marrow transplantation in the management of hematologic malignancies. The summaries included in our report are aimed at assisting busy medical practitioners in the clinical decision making for the benefit of patients under their care and to encourage clinicians to form their own opinions by reading and interpreting data presented in the original full-text articles.
Dreyling et al. (2005) reported results of a prospective randomized trial that suggests a substantially improved progression-free survival in patients with mantle-cell lymphoma after myeloablative radiochemotherapy followed by autologous stem cell transplantation (ASCT). Richardson et al. (2005) compared bortezomib with high-dose dexamethasone in patients with relapsed multiple myeloma, suggesting that bortezomib is superior for the treatment of multiple myeloma in patients who have had a relapse after one to three previous therapies. Ribera et al. (2005) reported on the results of the PETHEMA ALL-93 trial, which compared three options of postremission therapy in adults with high-risk acute lymphoblastic leukemia (ALL). Their findings suggest that allogeneic stem cell transplantation (SCT) does not produce a better outcome than ASCT or chemotherapy in adults with high-risk ALL when a family donor is available. Feugier et al. (2005) presented long-term results of treating elderly patients with diffuse large B-cell lymphoma with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) compared with rituximab plus CHOP (R-CHOP). This randomized trial, conducted by the Groupe d'Etudes des Lymphomes de l'Adulte (GELA), reported a substantially improved event-free survival, progression-free survival, disease-free survival, and overall survival in patients treated with the R-CHOP combination. Diedrich et al. (2005) investigated the impact of lowering the platelet count threshold for prophylactic platelet transfusion in a prospective randomized trial. They found that a prophylactic platelet transfusion trigger of less than 10 x 109 platelets/L instead of less than 30 x 109 plateletes/L in allogeneic hematopoietic progenitor cell transplant recipients is safe and resulted in a decreased use of platelets. Deconinck et al. (2004), on behalf of the French Groupe Quest-Est Leucémies et Autres Maladies du Sang (GOELMS), compared an immunochemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon) with high-dose chemotherapy followed by purged autologous stem-cell transplantation in patients with advanced follicular lymphoma. Those treated with high-dose therapy had a higher response rate and a longer median event-free survival. However, this approach did not translate into a better survival rate because of an excess of secondary malignancies. The Stem Cell Trialists' Group, an international collaborative from Africa, Europe, and the United States (2005), provided data from an individual patient data meta-analysis of nine randomized trials suggesting that allogeneic peripheral blood stem cell transplantation (PBSCT) is associated with a decreased relapse rate in hematologic malignancies and improvement in overall and disease-free survival in patients with late-stage disease. Ballova et al. (2005) provided results of a prospective randomized trial of the German Hodgkin Study Group (GHSG) comparing two chemotherapy regimens (BEACOPP baseline) and (COPP–ABVD) and found no substantial differences for complete remission, overall survival, and freedom from treatment failure at 5 years for elderly patients. Levy et al. (2005) reported a meta-analysis on data from 575 patients with multiple myeloma to assess the long-term effects of high-dose therapy followed by ASCT (HDT–ASCT) compared with conventional therapy. This meta-analysis failed to demonstrate any clear difference in survival for HDT–ASCT over conventional therapy for first-line treatment of myeloma. However, HDT–ASCT delayed time to relapse, i.e., 14.5 months' benefit in mean time without symptoms of disease or toxicity (TWiST). Finally, Noordijk et al. (2005) provided the first results of the EORTC-GELA H9 randomized trials, that is, the H9-F trial (i.e., comparing three radiation dose levels) and the H9U trial (i.e., comparing three chemotherapy schedules) in patients with favorable or unfavorable early-stage Hodgkin lymphoma (HL).
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NEW CHMG REVIEWS OR PROTOCOLS |
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TopNotesIntroductionNew chmg reviews or...Published trials |
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None.
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PUBLISHED TRIALS |
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TopNotesIntroductionNew chmg reviews or...Published trials |
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Indolent and Aggressive Non-Hodgkin Lymphoma
Advanced Follicular Lymphoma
Deconinck E, Foussard C, Milpied N, Bertrand P, Michenet P, Cornillet-LeFebvre P, et al., for GOELAMS. High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood 2005;105:3817–23.
Clinical background. Follicular lymphomas are a subgroup of B-cell non-Hodgkin lymphoma that account for 15%–30% of newly diagnosed lymphomas. Median survival varies from 5 to 10 years, depending on the prognostic factors at diagnosis and the response to first-line treatment. The role of high-dose therapy as a salvage treatment for patients with relapsing follicular lymphoma is still of interest and remains controversial.
Contribution. This prospective trial recruited 172 patients (aged 18–60 years) with previously untreated histologically proven follicular lymphoma that was classified according to the National Cancer Institute (NCI) Working Formulation Groups (B, C, D lymphoma) and reviewed according to the Revised European-American Lymphoma (REAL) classification of the International Lymphoma Study Group (grades 1–3 center follicle lymphoma). Patients were randomly assigned to receive either standard chemotherapy of cyclophosphamide at 600 mg/m2, doxorubicin 25 mg/m2, and teniposide 60 mg/m2—all administered intravenously on day 1—and prednisone 40 mg/m2 orally on days 1–5 or high-dose therapy, consisting of intravenous vindesine at 3 mg/m2 on day 1, cyclophosphamide 1500 mg/m2 on day 2, doxorubicin 80 mg/m2 on day 2, and prednisolone 50 mg/m2 on days 1–5 every 3 weeks. Patients in complete response (CR), very good partial response (VGPR), or partial response (PR) in the high-dose arm after the second or third cycle continued on stem cell harvesting. Adverse events, including grades 3–4 hematologic toxic effects, were observed in three patients during the CHVP cycles. Fifteen patients had severe infections or septicemia after high-dose cyclophosphamide and total-body irradiation. Secondary cancers (n = 10) after autografting developed between 12 and 45 months and included leukemia, myelodysplasia, breast cancer, renal, and prostate cancer.
Implications for practice. The high rate of secondary malignancies observed in the high-dose treatment arm are of concern. ASCT with ex vivo purging cannot be considered as the standard first-line treatment of follicular lymphoma for patients younger than 60 years with high tumor burden.
Key study features are as follows.
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Diffuse Large B-Cell Lymphoma
Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. J Clin Oncol 2005;23:4117–26.
Clinical background. Diffuse large B-cell lymphoma is the most frequently diagnosed non-Hodgkin lymphoma (NHL), and more than 50% of these patients are older than 60 years. For 25 years, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy was considered the "gold standard." New treatment schedules with the monoclonal antibody rituximab (R) have demonstrated efficacy in diffuse large B-cell lymphoma alone and in combination with the CHOP regimen (R-CHOP).
Contribution. This updated analysis of a medium-sized French study randomized 399 previously untreated patients aged 60–80 years with diffuse large B-cell lymphoma according to the WHO classification and with stage II, III, or IV disease to either CHOP alone or to R-CHOP chemotherapy. Patients treated with CHOP received cyclophosphamide at 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 up to a maximum dose of 2 mg on day 1, with prednisone 40 mg/m2 daily on days 1–5. Patients were treated every 3 weeks for eight cycles. Patients treated with R-CHOP received rituximab 375 mg/m2 on day 1 for each of the eight cycles. If patients developed grade 4 neutropenia or febrile neutropenia after a cycle of CHOP or R-CHOP, all subsequent cycles were administered with granulocyte colony-stimulating factor (G-CSF). There were 19 patients presenting with secondary malignancies, 10 in the CHOP and nine in the R-CHOP arm. After a median follow-up of 5 years, 26% more patients were alive in the R-CHOP arm than the CHOP arm.
Implications for practice. Elderly patients with diffuse large B-cell lymphoma benefit from the combination chemotherapy of rituximab and CHOP. Data suggest that this treatment schedule should become the standard, as it leads to 5-year survival benefit for this specific patient group.
Key study features are as follows.
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Low-Grade Lymphoma
Mantle-Cell Lymphoma
Dreyling M, Lenz G, Van Hoof A, Gisselbrecht C, Schmits R, Metzner B, et al. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood 2005;105:2677–84.
Clinical background. Advanced-stage mantle-cell lymphoma is characterized by an aggressive clinical progression and poor prognosis with a median survival of only 3–4 years and a low proportion of long-term survivors. To improve outcomes in mantle-cell lymphoma, consolidation high-dose therapy in combination with ASCT is being tested to define the impact of this approach more precisely.
Contribution. This multicenter study randomly assigned ized 122 patients aged between 18 and 65 years with previously untreated advanced mantle-cell lymphoma (Anne Arbor stage III and IV) up front to either myeloablative radiochemotherapy followed by ASCT or to interferon alpha (IFN-
) maintenance after completion of induction therapy. For initial cytoreductive therapy, four to six cycles of different CHOP-like regimens were applied. Most patients received CHOP (intravenous [i.v.] cyclophosphamide at 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [up to a maximal dose of 2 mg/m2]) on day 1 and prednisone 100 mg/m2 orally on days 1–5, or the combination of CHOP and rituximab (375 mg/m2 i.v.) after prophylactic application of antipyretic and antihistamine premedication on day zero. Patients randomly assigned to ASCT received intensified mobilization chemotherapy with Dexa-BEAM (dexamethasone 3 x 8 mg orally, days 1–10; BCNU [1,3-bis (2-chloroethyl)-1-nitrosurea], 60 mg/m2 i.v. day 2; melphalan 20 mg/m2 i.v. day 3; etoposide 75 mg/m2 i.v. days 4–7; cytarabine 2 x 100 mg/m2 i.v. days 4–7; granulocyte colony-stimulating factor (G-CSF) on day 11. Patients randomly assigned to the IFN- maintenance arm received two additional courses of conventional chemotherapy to balance the mobilization regimen. Myeloablative therapy was performed within 2 months of mobilization and consisted of a total-body irradiation (TBI) of 12 Gy, fractionated on days –6 to –4; pulmonary dosage was limited to 8 Gy.
Treatment-associated toxic effects were higher in the ASCT study arm (i.e., anemia, leukocytopenia, granulocytopenia, and thrombocytopenia). Infections due to cytopenia occurred in 85% of patients in the ASCT arm compared with only 22% of patients in the IFN- study arm.
Implications for practice. Myeloablative radiochemotherapy is a feasible and effective treatment option in the therapy of MCL when applied in first remission. Thus this approach may be offered to patients aged 65 years or younger. However, since many patients will still relapse after ASCT, additional treatment schedules, such as in vivo purging with rituximab or antibody maintenance, are required to further improve the prognosis of patients with MCL.
Key study features are as follows.
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Multiple Myeloma
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or high-dose dexamethasone for relapsed myeloma. N Engl J Med 2005;352:2487–98.
Clinical background. In newly diagnosed disease, only high-dose chemotherapy followed by autologous stem cell transplantation has been shown to provide survival benefit. The optimal therapy for relapsed myeloma is not established, but high-dose dexamethasone is commonly used. The proteasome inhibitor bortezomib induces apoptosis and reverses drug resistance of multiple myeloma cells; the drug received U.S. Food and Drug Administration (FDA) approval for the treatment of relapsed and refractory multiple myeloma.
Contribution. This international open-label multicenter study randomly assigned 669 patients with measurable progressive disease after one to three previous treatments. Patients received either intravenous (i.v.) bortezomib or oral dexamethasone. Bortezomib was administered i.v. at 1.3 mg/m2 on days 1, 4, 8, and 11 of cycles 1–8 (21-day cycles) and on days 1, 8, 15, and 22 of cycles 9–11 (35-day cycles) for a maximum treatment period of 273 days. Oral dexamethasone (40 mg) was given on days 1–4, 9–12, and 17–20 of cycles 1–4 (35-day cycles) and on days 1–4 of cycles 5–9 (28-day cycles for a maximum treatment period of 280 days). The final analysis showed that patients taking bortezomib had a statistically significant prolongation of the median time to disease progression (P<.001) and a statistically significantly improved survival rate at 1-year follow-up (P = .003) compared with patients receiving dexamethasone. The rates of grade 3 and 4 adverse events (including gastrointestinal events, thrombocytopenia, and peripheral neuropathy) were similar in both groups. However, the overall rate of grade 3 events was 61% in the bortezomib group versus 44% of patients receiving dexamethasone (P<.01).
Implications for practice. Patients with multiple myeloma who have had a relapse after one to three previous therapies benefit from being treated with bortezomib, a proteasome inhibitor. However, despite the apparent superiority of bortezomib to high-dose dexamethasone, the degree of adverse events associated with bortezomib must always be considered.
Key study features are as follows.
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Acute Lymphoblastic Leukemia
Ribera JM, Oriol A, Bethencourt C, Parody R, Hernandez-Rivas JM, Moreno MJ, et al., on behalf of the PETHEMA Group, Spain. Comparison of intensive chemotherapy, allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukaemia. Results of the PETHEMA ALL-93 trial. Haematologica 2005;90:1346–56.
Clinical background. The optimal postremission therapy for adults with high-risk ALL is not well established. Despite its use for more than 20 years, the value of SCT in the treatment of ALL remains controversial. The number of controlled published or ongoing trials is remarkably small, and many such studies include both standard- and high-risk patients. Thus, controlled trials with a focus on patients with a specific risk category of ALL are of particular interest.
Contribution. This complex Spanish study treated 222 adult patients with high-risk ALL. Initially, all patients received a standard five-drug/5-week induction course consisting of intravenous (i.v.) or oral (p.o.) vincristine (30 mg/m2 i.v.); prednisone (60 mg/m2, 30 mg/m2, 15 mg/m2 i.v./p.o.); daunorubicin (30 mg/m2 i.v.); L-asparaginase (10 000 IU/m2 i.v.) and cyclophosphamide (1000 mg/m2 i.v.). Patients in complete remission (CR) with a human leukocyte antigen (HLA)–identical sibling were then assigned to allogeneic SCT, whereas those remaining were randomly assigned to either ASCT or delayed intensification chemotherapy with the same cycles used in the early intensification phase. The conditioning regimen for allogeneic SCT or ASCT was cyclophosphamide (60 mg/kg on 2 consecutive days) and fractionated total body irradiation (TBI) for a total of 12 Gy. The delayed intensive chemotherapy schedule consisted of vincristine (2 mg, i.v.), methotrexate (3 g, i.v.), cytarabine (2 g/m2/12 hours, i.v.), L-asparaginase (25 000 IU/m2, i.v./intramuscular (i.m.); dexamethasone (20, 10, 5, 2.5 mg/m2, i.v./p.o.), and mercaptopurine (100 mg/p.o.). Unfortunately, the study did not provide information on the occurrence of adverse events. The study report mentioned no transplant- or chemotherapy-related toxic effects.
Implications for practice. This study failed to prove that, when a family donor is available, allogeneic SCT produces a better outcome than ASCT or chemotherapy in adults for high-risk ALL. The absence of information on therapy-related adverse effects is unfortunate and would have been useful.
Key study features are as follows.
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Transfusion Medicine
Diedrich B, Remberger M, Shanwell A, Svahn BM, Ringdén O. A prospective randomized trial of a prophylactic platelet transfusion trigger of 10 x 109 per L versus 30 x 109 per L in allogeneic hematopoietic progenitor cell transplant recipients. Transfusion 2005;45:1064–72.[CrossRef][Web of Science]
Clinical background. Hematopoietic progenitor cell transplantation (HPCT) is a well-established therapy for hematologic malignancies, severe aplastic anemia, and some metabolic disorders. The impact of lowering the platelet count threshold for prophylactic platelet transfusion on bleeding and platelet use in allogeneic HPCT recipients continues to be debated.
Contribution. This Swedish trial randomly assigned patients undergoing allogeneic HPCT to receive prophylactically platelet transfusions when their morning PLT count decreased below 10 x 109/L (group T10) or 30 x 109/L (group T30).
All platelet concentrates (packed cells) were prepared according to institutional policy and irradiated before transfusion. Red blood cells (RBCs) were transfused when hemoglobin levels decreased below 80 g/L. The number of PLT units transfused was statistically significantly lower in group T10 (median = 4; range 0–32) than in group T30 (median = 10; range 0–48; P<.001). Keeping the patients' platelet count at a higher level required a median of six more platelet transfusions. For clinical outcomes (i.e., bacteremia, engraftment, graft-versus-host disease [GVHD], hospital stay, death, and survival) or the median total number of RBC transfusions given, no statistically significant differences were found, i.e., 18% (14/79) for group T10 and 15% (13/87) in group T30. The incidence of bleeding (WHO grades 2–4) was similar in both groups 14 (18%) in group T10 versus 13 (15%) in group T30.
Implications for practice. The threshold of less than 10 x 109 /L instead of 30 x 109/L as trigger for prophylactic platelet transfusion in allogeneic hematopoietic progenitor cell transplant recipients may be useful, as it reduces the number of transfused platelet units overall. Safety aspects are not clear, however, as overall survival (OS) was not the primary endpoint. Furthermore, the study was not adequately powered to show that survival is not affected.
Key study features are as follows.
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Other Published Trials and Meta-Analyses of Potential Interest
Ballova V, Rüffer JU, Haverkamp H, Pfistner B, Müller-Hermelink HK, Dühmke E, et al. A prospective randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP–ABVD (study HD9 elderly). Ann Oncol 2005;16:124–31.
This trial, considered the first multicenter randomized study in 75 elderly patients with advanced-stage Hodgkin disease (HD), comparing a standard COPP–ABVD regimen (cyclophosphamide, vincristine, procarbazine, and prednisone alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine with a more aggressive experimental BEACOPP schedule (cyclophosphamide, doxorubicin, etoposide, procarbazine, prednisone, bleomycin, and vincristine). In summary, there was no statistically significant difference between COPP–ABVD and BEACOPP for complete remission (76%), overall survival (50%), and freedom from treatment failure (FFTF) (46%) at 5 years.
Al Jurf M, Aranha F, Annassetti C, Apperley JF, Baynes R, Bensinger WI, et al., for the Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol 2005;23:5074–87.
This individual patient data meta-analysis investigated the effects of PBSCT versus bone marrow transplantation (BMT). From nine analyzed trials it was found, overall, that allogeneic PBSCT was associated with a statistically significant improvement in disease-free survival over BMT (odds ratio [OR] = 0.80; 95% confidence interval [CI] = 0.67 to 0.97; P = .02; 59% vs. 53% at 3 years and 54% vs. 47% at 5 years, respectively). There was no statistically significant difference in overall survival between PBSCT and BMT (OR = 0.87; 95% CI = 0.72 to 1.06; P = .17). In summary, PBSCT is associated with a decreased relapse rate in hematological malignancies and in improvement in overall and disease-free survival in patients with late-stage disease. PBSCT is also associated with a high risk of extensive chronic graft-versus-host disease (GVHD).
Lévy V, Kathsahian S, Fermand JP, Yves MJ, Chevret S. A meta-analysis on data from 575 patients with multiple myeloma randomly assigned to either high-dose therapy or conventional therapy. Medicine 2005;84:250–60.[CrossRef][Medline]
This meta-analysis (MA) used individual data of 575 patients, all with medium follow-up of 5 years or more, from three French randomized clinical trials from 1990 to 1998. Under investigation were the long term-benefits of high-dose therapy followed by ASCT (HDT–ASCT) compared with conventional therapy (combined chemotherapy consisting of lomustine, cyclophosphamide, melphalan, and total-body irradiation [TBI]). Outcomes were survival, treatment-related mortality, and time without symptoms of disease toxicity of treatment (TWiST). Compared with conventional therapy, HDT–ASCT did not statistically prolong long-term survival (hazard ratio = 0.887; 95% CI = 0.735 to 1.072). In contrast, a mean gain of 14.5 months (95% CI = 9.9 to 19.1 months) in TWiST was observed in the HDT–ASCT group compared with conventional therapy.
Noordijk EM, Thomas J, Fermé C, van't Veer MB, Brice P, Diviné M, et al. First results of the EORTC-GELA H9 randomized trials: the H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin's lymphoma (HL). J Clin Oncol 2005; ASCO Annual Meeting Proceedings. Vol. 23, No. 16S (June 1 Supplement), 6505.
This study, available only as an abstract at the time of writing, was considered important enough for inclusion in our report. A total of 1591 patients with stage I–II Hodgkin lymphoma were enrolled from October 1998 to May 2004 into two trials based on four prognostic factors, i.e., age, symptoms, number of involved areas, and mediastinal–thoracic ratio. The H9-F study compared 36-Gy involved-field radiotherapy (IF-RT) versus 20-Gy IF-RT versus no RT in patients in complete remission (CR after six cycles of EBVP chemotherapy [epirubicin, bleomycin, vinblastine, prednisone]). The H9-U trial compared six cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) versus four cycles of ABVD versus four cycles of BEACOPP (cyclophosphamide, doxorubicin, etoposide, procarbazine, prednisone, bleomycin, vincristine), followed by 30-Gy IF-RT in all arms. The study purports that, in patients with favorable Hodgkin lymphoma who achieve CR after six cycles of EBVP, omission of IF-RT leads to an unacceptable failure rate. In contrast, an IF-RT dose reduced to 20 Gy provides early results equivalent to those of an IF-RT dose of 36 Gy. In unfavorable Hodgkin lymphoma patients, similar event-free survival (EFS) rates are observed when the number of ABVD cycles is reduced from six to four. BEACOPP is not more efficient but is more toxic.
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NOTES |
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TopNotesIntroductionNew chmg reviews or...Published trials |
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1 "Dropouts" refers to participants who withdrew consent, were unavailable for follow-up, or were not evaluable.
2 "Protocol violations" refers to participants who, e.g., did not receive the intended treatment, switched arms, withdrew consent, or were determined ineligible after randomization.
The editorial base of the Cochrane Haematological Malignancies Group is funded as part of the Competence Network Malignant Lymphoma by the German Ministry of Education and Research (BMBF).
Thilo Kober was the CHMG executive officer until March 2006, and Andreas Engert is the CHMG coordinating editor. Julia Bohlius and Helge Hülsewede are members of the CHMG editorial base.
Andreas Engert coauthored one of the randomized trials discussed in this report.
There are no financial conflicts of interest associated with this report.
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