Annals of Oncology Advance Access originally published online on October 27, 2006
Annals of Oncology 2007 18(1):136-142; doi:10.1093/annonc/mdl348
© 2006 European Society for Medical Oncology
hematologic malignancies |
Initial chemotherapy with mitoxantrone, chlorambucil, prednisone impairs the collection of stem cells in patients with indolent lymphomas—results of a randomized comparison by the German Low-Grade Lymphoma Study Group
1 Department of Internal Medicine III, Ludwig-Maximilians University, Munich Grosshadern
2 Institute of Medical Informatics, Biometry and Epidemiology, University of Munich
3 Department of Hematology and Oncology, Charité Campus Berlin-Buch
4 Department of Hematology and Oncology, Charité Berlin Campus Virchow-Klinikum
5 Division of Hematology and Oncology, University Rostock
6 Department of Internal Medicine III, University of Mainz
7 Department of Hematology, Hemostasis and Oncology, Hannover Medical School
8 Department of Hematology and Oncology, Georg-August University, Göttingen, Germany
* Correspondence to: Dr W. Hiddemann, Department of Internal Medicine III, Ludwig-Maximilians University, Marchioninistrasse 15, 81377 Munich, Germany. Tel: +49-89-7095-2550; Fax: +49-89-7095-5550; E-mail: Wolfgang.Hiddemann{at}med.uni-muenchen.de
 |
Abstract |
|---|
 Top Abstract introductionpatients, protocol and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Myeloablative radio-chemotherapy with subsequent autologous stem cell transplantation (ASCT) significantly prolongs progression free and probably overall survival in follicular lymphoma (FL) in first remission. The current trial explored prospectively the rate of successful stem cell mobilization in patients with advanced stage FL after initial therapy with either Mitoxantrone, Chlorambucil, Prednisone (MCP) or Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (CHOP) as part of a prospective randomized comparison of both regimens. ASCT patients received Dexa-BEAM (Dexamethasone, BCNU, Melphalan, Etoposide, Cytarabine) for mobilization of stem cells. Stem cells were collected and a minimum of 2 x 2.0 x 106/kg bw CD34+ was required for ASCT.
Of 79 evaluable patients, 58 (73%) had follicular lymphoma, 13 (16%) mantle cell lymphoma and 8 (10%) lymphoplasmacytic lymphoma.
In the 45 patients assigned to CHOP, stem cell collection was successful in 42 cases (93%, 95% CI 82% to 99%). This high mobilization rate after CHOP could be confirmed in 61 subsequent patients (87%). In contrast, after MCP therapy stem cell collection was successful in only 15 of 34 patients (44%, 95% CI 27% to 62%; P = 0.0003).
In conclusion, initial therapy with MCP significantly impairs the ability to collect stem cells and should be avoided for first line therapy of younger patients potentially qualifying for high dose consolidation and ASCT in first remission.
Key words: chemotherapy, indolent lymphoma, stem cell collection
|
introduction |
|---|
|
TopAbstractintroductionpatients, protocol and methodsresultsdiscussionAcknowledgementsReferences |
|---|
Follicular lymphoma (FL) is clinically characterized by an indolent course with a slow progression and a median survival time ranging from 7 to 10 years [1]. During the last decades, various chemotherapy combinations have failed to improve overall survival (OS) [2]. In an attempt to improve the outcome of patients with advanced-stage FL, myeloablative therapy followed by autogeneic stem cell transplantation (ASCT) was investigated both in relapsed cases as well as in first remission. Initial phase II studies have displayed a significantly improved progression-free survival (PFS) in relapsed FL and more importantly, a recently published phase III trial indicated also an improvement of OS [3–7]. Another most promising approach is the addition of rituximab (Roche) to conventional chemotherapy (R-chemo). Several randomized trials demonstrated a significant improvement of PFS and in some of them even of OS [8–11]. Nevertheless, interstudy comparison revealed substantial differences in outcome in relation to the applied cytostatic combination.
In how far these results may influence the requirement of subsequent myeloablative therapy with ASCT or whether the combination of R-chemo followed by myeloablative treatment and ASCT may even cure a fraction of patients with advanced-stage FL remains currently unanswered. Hence, research on the intensive treatment option is ongoing.
Progenitor cell mobilization is an essential part of myeloablative protocols. According to previous studies, 10%–30% of patients are difficult to mobilize or fail progenitor cell mobilization [12, 13]. The number of cycles and duration of previous chemotherapy, the interval between previous chemotherapy and mobilization and exposure to stem cell-toxic (especially alkylating) drugs have been identified as important predictors of peripheral blood stem cell yield. Accordingly, Drake et al. [14] proposed a scoring system for previous chemotherapy predicting progenitor cell yield.
The German Low-Grade Study Group (GLSG) evaluated this concept in first remission after initial chemotherapy induction with either CHOP [cyclophosphamide (CPM) (Baxter Oncology), vincristine (VCR) (Cell pharm), doxorubicin (DOX) (Pharmacia) and prednisone (Merck)] or MCP (mitoxantrone (Wyeth), chlorambucil (GlaxoSmithKline) and prednisone). Responders up to 60 years were subsequently assigned to either myeloablative radiochemotherapy and ASCT or to interferon-
(IFN-) (Roche) maintenance [15].
The efficacy of successful stem cell mobilization after CHOP versus MCP in patients assigned to the ASCT arm was one of the primary trial end points.
|
patients, protocol and methods |
|---|
|
TopAbstractintroductionpatients, protocol and methodsresultsdiscussionAcknowledgementsReferences |
|---|
eligibility criteria
This randomized trial was initiated in May 1996. Patients
18 years of age with previously untreated advanced-stage III or IV indolent lymphomas including FL, mantle cell lymphoma (MCL) and lymphoplasmacytic lymphoma (LPL) according to the current World Health Organisation (WHO) classification were eligible [16]. Confirmation of histologic diagnosis by central pathology review was mandatory. Similar to the British National Lymphoma Investigation (BNLI) criteria, patients with FL or LPL had to be in need of therapy as defined by (i) the presence of B-symptoms, (ii) hematopoietic insufficiency (granulocytes <1500/µl, hemoglobin <10 g/dl and platelets <100,000/µl), (iii) rapid progression of the disease (at least by 50% in the past 6 months), and/or (iv) bulky disease (largest diameter >5 cm). In patients with advanced-stage MCL, therapy was initiated immediately.
Patients with disease potentially curable by radiotherapy, as well as patients with a poor performance status (Eastern Cooperative Oncology Group >2) were excluded. In addition, patients with seriously impaired cardiac, pulmonary, hepatic (AST/ALT three times of upper limits and/or bilirubin level 2.0 mg/dl) or renal function (creatinine level >2.0 mg/dl) were not enrolled.
randomization and treatment protocols
Eligible patients underwent a central randomization procedure for the initial cytoreductive regimens (MCP versus CHOP). Randomization was stratified for histology (FL versus LPL versus MCL), age (<60 versus 60 years) and the number of International Prognostic Index (IPI) risk factors other than age (
2 versus 3).
The MCP regimen comprised of mitoxantrone 8 mg/m2 i.v. days 1–2, chlorambucil 3 mg/m2 three times daily by mouth days 1–5 and prednisone 25 mg/m2 by mouth days 1–5. It was repeated every 4 weeks. In case of a hematologic nadir with granulocyte counts below 1000/µl or platelet counts <75 000/µl, doses of mitoxantrone and chlorambucil were reduced by 20%.
The CHOP protocol consisted of i.v. applications of cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2 (maximum 2 mg), doxorubicin 50 mg/m2 (all day 1) and prednisone 100 mg/m2 by mouth days 1–5 and was repeated every 3 weeks. In case of post-therapeutic hematologic nadir, doses of cyclophosphamide and doxorubicin were reduced by 20%. In case of peripheral neurotoxicity, vincristine was terminated and treatment was continued with cyclophosphamide, doxorubicin and prednisone only. Both regimens were given for four to six cycles.
Patients <60 years underwent a second randomization after completion of the second induction course for ASCT or IFN- maintenance (3 x 5 Mio IE/week).
Patients in the ASCT arm with response [complete remission (CR) + partial remission (PR)] to induction therapy received intensified mobilization chemotherapy with Dexa-BEAM [dexamethasone (Merck) 3 x 8 mg by mouth, days 1–10; carmustine (Bristol-Myers Squibb) 60 mg/m2 i.v., day 2; melphalan (GlaxoSmithKline) 20 mg/m2 i.v., day 3, etoposide (Baxter Oncology) (VP-16) 75 mg/m2 i.v., days 4–7; cytarabine (Cell pharm) 2 x 100 mg/m2 i.v., days 4–7, and granulocyte colony-stimulating factor (G-CSF) (Neupogen, Amgen) initiated on day 11]. Myeloablative therapy included 2 x 60 mg/kg CPM and 12 Gy total body irradiation followed by ASCT of at least 2 x 106 CD34+ cells.
stem cell mobilization criteria and evaluation
For mobilization of peripheral stem cells, G-CSF was started directly after Dexa-BEAM regimen at a dose of 5–10 µg/kg body weight and continued until the completion of stem cell harvest. Stem cell separation was carried out after achievement of white blood cell (WBC) count >1000/mm3 following the WBC nadir and CD34+ cell >10/µl (minimal 2 x 2 x 106/kg body weight CD34+ cells for transplantation and back up). Separation and storage were done according to local standard procedures. No enrichment of stem cell subpopulations or in vitro purging was carried out.
If the target dose of CD34+ cells was not achieved, an additional attempt with G-CSF only was started 14–21 days later. G-CSF was applied at a dose of 2 x 10–15 µg/kg body weight and continued until the completion of stem cell harvest. Stem cell separation was carried out after reaching 20/µl CD34+ cells in peripheral blood. Stem cell mobilization was considered as failure if that attempt was unsuccessful.
definition of response
Response to therapy was assessed after every two cycles of CHOP or MCP and 4 weeks after completion of the last course. Response evaluation consisted of physical examination, determination of blood count and lactate dehydrogenase (LDH) level, ultrasound of the abdomen and CT of previously involved areas. In patients otherwise fulfilling the criteria of CR, bone marrow biopsy was carried out. Except for CT of previously involved areas, which was repeated every 6 months, these analyses were carried out every 3 months as follow-up.
Response was defined according to the International Working Group criteria [17]. Hence, CR meant the elimination of all lymphoma manifestations for at least 4 weeks, whereas PR was defined as a reduction of disease manifestations by at least 50% for >4 weeks. The appearance of new nodal or extranodal manifestations or the enlargement of pre-existing lymphoma manifestations by >25% was considered disease progression. Time to treatment failure (TTF) was defined as the interval between the start of treatment and the documentation of resistance to initial therapy, progressive disease or death. Response duration (RD) was defined as the interval from the end of successful induction therapy to the documentation of progression or death, and OS was defined as the interval between the start of treatment and death. Analyses were carried out on an intention-to-treat basis without censoring for patients' refusing the scheduled treatment in remission or receiving other unplanned therapies. Frequency and severity of adverse effects were recorded according to WHO toxicity criteria.
statistical analyses
Besides the rate of CRs as primary efficacy end point, the success rate of stem cell mobilization was included as an additional primary end point for the subgroup of patients who were scheduled for ASCT. The respective results for efficacy have been reported elsewhere [18].
The success rate of stem cell mobilization was monitored by means of the restricted sequential procedure for Fisher's exact test, with planned interim analyses, in order to allow an early stopping of randomization in case of a large difference between the groups [19]. The sample size was calculated to detect an unacceptable low success rate of 75% as compared with the anticipated standard rate of 90%–95% with a power of 97.5% and a significance level of 5% two-sided. Responding patients were assessable if mobilization with Dexa-BEAM had been initiated. The significance of the primary end point was calculated with respect to the sequential design, secondary group comparisons were done by means of two-sided Fisher's exact tests. Statistical analyses used PEST version 3 and SAS version 8.2.
study conduct
The study adhered to the latest version of the Helsinki declaration. The study protocol was approved by the local ethics committees of the participating centers and all patients gave their written informed consent after having been informed about the investigational nature of the trial.
|
results |
|---|
|
TopAbstractintroductionpatients, protocol and methodsresultsdiscussionAcknowledgementsReferences |
|---|
patients characteristics
Between May 1996 and December 1998, a total of 506 patients were recruited into the study. In all, 255 patients <60 years of age were potentially eligible for later ASCT and were randomized for initial chemotherapy with CHOP or MCP. Of the 118 patients randomized to the ASCT arm after two cycles of induction therapy, 79 patients were assessable for the comparison of stem cell mobilization (Figure 1).
|
A total of 45 patients were treated with CHOP and 34 patients were treated with MCP. A total of 58 patients (73%) had FL, 13 patients (16%) had MCL and eight patients (10%) had LPL. In all, 30% of the patients presented with B-symptoms, 29% patients had an elevated LDH level and 83% patients were diagnosed with stage IV disease. In addition, in the 72 patients assessable for the IPI, 46% had a low risk, 41% had a low-intermediate risk and 6% had a high-intermediate risk IPI. Patients characteristics of the two study arms were not significantly different and are summarized in Table 1.
|
Due to the large difference between the arms, the sequential statistical monitoring showed a very early decision in favor of CHOP and randomization was stopped in July 1998. Since the randomization between ASCT and IFN-
maintenance was continued, subsequent patients were assigned to CHOP induction therapy and 61 additional patients randomized to ASCT were assessable for stem cell mobilization.
response to chemotherapy
In the CHOP arm, 40 of 217 randomized patients achieved a CR (18%) in comparison to 27 (14%) of 198 in the MCP arm (P = 0.066). The overall response rate (CR + PR), however, was significantly higher after CHOP as compared with MCP (86% versus 77%, P = 0.0094), whereas there was no significant difference in RD, TTF or OS between both regimens [18].
success of stem cell mobilization
Forty two of 45 patients treated with CHOP had successful stem cell mobilization [93%, 95% confidence interval (CI) 82% to 99%], whereas stem cell mobilization was successful in only 15 of 34 patients treated with MCP (44%, 95% CI 27% to 62%, P = 0.0003, Figure 2).
|
Similar results were obtained in the intention-to-treat analysis of the 118 patients randomized to CHOP or MCP and to the ASCT arm (except those marked with an asterisk in Figure 1).
In 44 of 49 patients treated with CHOP, stem cell mobilization was successful (90%, 95% CI 78% to 97%), whereas only in 17 of 42 patients treated with MCP, stem cell mobilization was successful (40%, 95% CI 26% to 57%, p < 0.0001).
In the cohort of 61 patients subsequently assigned to CHOP and ASCT, 53 patients showed successful stem cell mobilization (87%, 95% CI 76% to 94%).
toxicity after Dexa-BEAM
Hematologic toxicity was the predominant side-effect after Dexa-BEAM. Severe anemia grade 3/4 occurred in 18%, thrombocytopenia grade 3/4 was detected in 91% and severe granulocytopenia grade 3/4 in 93% patients, whereas severe infection grade 3/4 was observed in only 11%. Non-hematologic toxic effects such as nausea/vomiting (grade 3/4) and mucositis (grade 3/4) were seen in 6% and 7%, respectively. Alopecia (grade 3/4) occurred in the majority of patients (81%). After induction with MCP, the frequency of toxic effects during Dexa-BEAM was significantly higher for bleeding, diarrhea, constipation and the skin and lower for neurotoxicity and alopecia, but besides alopecia, grade 3/4 toxic effects were equally low after the two induction regimens (Table 2).
|
|
discussion |
|---|
|
TopAbstractintroductionpatients, protocol and methodsresultsdiscussionAcknowledgementsReferences |
|---|
The present study shows that in the setting of Dexa-BEAM chemomobilization for autologous transplantation in patients with indolent lymphoma, the type of prior chemotherapy has significant impact on the stem cell yield. In a prospective randomized comparison it was demonstrated that initial therapy with MCP significantly impairs the ability to mobilize hematopoetic stem cells. While successful collection of stem cells could be achieved after CHOP in 93% of patients, this rate was significantly lower following MCP (44%; P = 0.0003). This difference is most likely due to the higher stem cell toxicity of mitoxantrone which might be intensified by additional chlorambucil. This hypothesis is supported by a recent report on an increasing incidence of secondary myelodysplastic syndromes and acute myeloid leukemias following MCP (5.1%) as compared with CHOP (1.3%, P = 0.14) in patients with indolent lymphomas [20]. Up to now there are only few in vitro studies analyzing the influence of cytotoxic drugs on hematopoetic stem cells. Mergenthaler et al. [21] reported on the precursor-cell toxicity of mitoxantrone and doxorubicin and showed that doxorubicin is less toxic than mitoxantrone at low concentrations but at higher concentration it was more toxic than mitoxantrone. Additionally, Chow et al. [22] could show in vitro a higher toxicity on mature stem cells after mitoxantrone than after doxorubicin. These findings might be considered as clinically irrelevant, since MCP is not a frequently used regimen outside Germany. Nevertheless, based on the excellent results combining MCP with rituximab which showed a high rate of CRs and a significant prolongation of the TTF and even of OS as compared with MCP alone, this regimen may become more popular. In addition, similar concerns about stem cell toxicity may also be relevant for other more frequently applied chemotherapeutic combinations such as combinations of fludarabine and cyclophosphamide (FC) with or without the addition of mitoxantrone. The FC regimen is often used in combination with rituximab for the first-line treatment not only of FL but also of chronic lymphocytic leukemia. Previous studies, however, indicated that the degree of initial bone marrow infiltration, the number and the kind of prior regimens, particularly when including alkylating agents, influence the ability to mobilize hematopoietic stem cells, regardless of the lymphoma subtype or the mobilization protocol [23–27].
Hematopoietic reconstitution after myeloablative therapy is strongly dependent on the number of transfused progenitor cells. Successful mobilization has been achieved after various chemotherapeutic combinations including ifosfamide, VP-16 and epirubicin [28, 29], dexamethasone, high-dose cytarabine and cisplatinum [30] or Dexa-BEAM [31] each followed by G-CSF with failure rates between 10% and 30%. Nevertheless, in terms of safety, progenitor cell yield, engraftment and tumor cell contamination, the optimal mobilization regimen still remains to be determined.
In the present trial, all patients received Dexa-BEAM for stem cell mobilization. The overall failure rate of 28% was higher than expected [13, 32], but exclusively due to the high failure rate after MCP of 56%. In contrast, unsuccessful collection of stem cells occurred in only 7% of cases after CHOP. The safety of CHOP could be confirmed on 61 subsequently treated patients in whom a failure rate of 13% was observed.
Drake et al. [14] proposed a scoring system for previous chemotherapy predicting progenitor cell yield. This system, however, could not be validated and no relation between this system and the apheresis yield was observed in subsequent trials [33]. In our study, MCP and CHOP would have a similar myelotoxic profile according to this score.
Previously, three large multicenter prospective randomized studies demonstrated a significant prolongation of remission duration after ASCT as compared with conventional, though no rituximab-containing, chemotherapy [34–36]. Preliminary data from a comparison of two consecutive trials of the GLSG rather indicate that ASCT after R-CHOP induction might produce a higher rate of long-term remissions as compared with R-CHOP followed by IFN- or ASCT after CHOP alone. Thus, it appears as a challenge for future therapeutic strategies to define the patient subpopulations that might benefit most from intensive, myeloablative therapy or who should be spared from such an approach. On the basis of the results of the present study MCP should not be offered to patients in whom subsequent myeloablative therapy and ASCT are planned. This may particularly relate to patients <65 years of age with an intermediate or high-risk profile according to Follicular Lymphoma International Prognostic Index [37, 38]. On the other hand, MCP and particularly R-MCP may be the preferred choice for other patients in whom the goal of therapy is directed towards achieving a complete and long-lasting remission but not a potential cure. In general, the spectrum of therapeutic approaches to patients with advanced-stage FL has recently expanded substantially. It ranges from single-agent treatment with rituximab over R-chemo combinations or different intensity up to a ‘total therapy’ concept as recently proposed by the GLSG. The challenge for clinicians is to select the most appropriate form of treatment of an individual patient not only on the basis of the biology of the disease but also on the basis of the constitution and will of the patient.
|
Acknowledgements |
|---|
|
TopAbstractintroductionpatients, protocol and methodsresultsdiscussionAcknowledgementsReferences |
|---|
The following persons and institutions participated in this trial: Fuss, Frenzel, Wruck, Humaine Klinikum Bad Saarow; Ludwig, Matylis, Robert Rössle Klinik Berlin; Dörken, Pezzutto, Massenkeil, Charité/Virchow-Klinikum Berlin; Possinger, Siegert, Sezer, Univ.-Klinik Charité/Campus Mitte Berlin; Hänel, Neser, Hänel, Klinikum Chemnitz GGmbh; Peter, Carl-Thiem-Klinikum Cottbus; Haas, Universitätsklinik Düsseldorf; Rösler, Klinik III der Universität Erlangen; Dührsen, Nückel, Klinik und Poliklinik Essen; Saal, Hartwigsen, Benk, St.-Franziskus-Hospital Flensburg; Mertelsmann, Finke, Medizinische Universitätsklinik Freiburg I. Br.; Trümper, Glaß, Binder, Universitätsklinik Göttingen; Zander, Kröger, Renges, Universitäts-Krankenhaus Eppendorf Hamburg; Schmidt, Kreiskrankenhaus Hameln; Ganser, Peest, Medizinische Hochschule Hannover; Pfreundschuh, Universitätsklinik des Saarlandes Homburg/Saar; Fauser, Klinik für Knochenmarktransplantation Idar-Oberstein; Höffken, Fricke, Wedding, Friedrich-Schiller-Universität Jena; Kneba, UKSH/Städt. Krankenhaus Kiel; Fetscher, Schmelar, Sana Kliniken—Krankenhaus Süd Lübeck; Wagner, Peters, Medizinische Universität Lübeck; Huber, Fischer, Heß, III. Medizinische Klinik Mainz; Hehlmann, Lengfelder, Kuhn, III. Klinik Mannheim; Neubauer, Schwella, Klinikum d. Philips-Universität Marburg; Bodenstein, Wöltjen, Klinikum II Minden; Wilhelm, Wandt, Lechner, Klinikum Nürnberg - 5. Klinik; Henning-Köhne, Metzner, Klinikum Oldenburg GGmbH; Maschmeyer, Rothmann, Haas, Ernst-Von-Bergmann-Klinik Potsdam; Andreesen, Krause, Mayer, Universitätsklinik Regensburg; Freund, Universitätsklinik Rostock; Biedermann, Kubin, Zumschlinge, Kreiskrankenhaus Traunstein; Döhner, Stilgenbauer, Viardot, Universität Ulm; Frickhofen, Fuhr, Jung, Dr. H. Schmidt-Kliniken Wiesbaden; Einsele, Weissinger, Reimer, Poliklinik der Universität Würzburg; Kreibich, Städtisches Klinikum H. Braun Zwickau.
Received for publication June 15, 2006. Revision received August 21, 2006. Accepted for publication August 23, 2006.
|
References |
|---|
|
TopAbstractintroductionpatients, protocol and methodsresultsdiscussionAcknowledgementsReferences |
|---|
1. Horning SJ. (2000) Follicular lymphoma: have we made any progress? Ann Oncol 11:23–27.
2. Horning SJ. (2003) Future directions in radioimmunotherapy for B-cell lymphoma. Semin Oncol 30:29–34.[Web of Science][Medline]
3. Weaver CH, Schwartzberg L, Rhinehart S, et al. (1998) High-dose chemotherapy with BUCY or BEAC and unpurged peripheral blood stem cell infusion in patients with low-grade non-Hodgkin's lymphoma. Bone Marrow Transplant 21:383–389.[CrossRef][Web of Science][Medline]
4. Voso MT, Martin S, Hohaus S, et al. (2000) Prognostic factors for the clinical outcome of patients with follicular lymphoma following high-dose therapy and peripheral blood stem cell transplantation (PBSCT). Bone Marrow Transplant 25:957–964.[CrossRef][Web of Science][Medline]
5. Freedman AS, Neuberg D, Mauch P, et al. (1999) Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 94:3325–3333.
6. Rohatiner A, Davis A, Apostolidis J, et al. (2005) High dose therapy (HDT) with autologous hematopoietic progenitor cell support as consolidation of remission in patients with follicular lymphoma (FL): long follow-up of St. Bartholomew's Hospital (SBH) and Dana-Farber Cancer Institute (DFCI) data [abstract]. Ann Oncol 16:Suppl 5, 62.
7. Schouten HC, Kvaloy S, Sydes M, et al. (2000) The CUP trial: a randomized study analyzing the efficacy of high dose therapy and purging in low-grade non-Hodgkin's lymphoma (NHL). Ann Oncol 11:91–94.
8. Herold M, Dolken G, Fiedler F, et al. (2003) Randomized phase III study for the treatment of advanced indolent non-Hodgkin's lymphomas (NHL) and mantle cell lymphoma: chemotherapy versus chemotherapy plus rituximab. Ann Hematol 82:77–79.[Web of Science][Medline]
9. Marcus R, Imrie K, Belch A, et al. (2005) CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417–1423.
10. Salles GA, Foussard C, Mounier N, et al. (2004) Rituximab added to IFN + CHVP improves the outcome of follicular lymphoma patients with a high tumor burden: first analysis of the GELA-GOELAMS FL- 2000 randomized trial in 359 patients. Blood 104:.
11. Hiddemann W, Kneba M, Dreyling M, et al. (2005) Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725–3732.
12. Micallef IN, Apostolidis J, Rohatiner AZ, et al. (2000) Factors which predict unsuccessful mobilisation of peripheral blood progenitor cells following G-CSF alone in patients with non-Hodgkin's lymphoma. Hematol J 1:367–373.[CrossRef][Medline]
13. Sugrue MW, Williams K, Pollock BH, et al. (2000) Characterization and outcome of ‘hard to mobilize’ lymphoma patients undergoing autologous stem cell transplantation. Leuk Lymphoma 39:509–519.[Web of Science][Medline]
14. Drake M, Ranaghan L, Morris TC, et al. (1997) Analysis of the effect of prior therapy on progenitor cell yield: use of a chemotherapy scoring system. Br J Haematol 98:745–749.[CrossRef][Web of Science][Medline]
15. Unterhalt M, Herrmann R, Tiemann M, et al. (1996) Prednimustine, mitoxantrone (PmM) vs cyclophosphamide, vincristine, prednisone (COP) for the treatment of advanced low-grade non-Hodgkin's lymphoma. German Low-Grade Lymphoma Study Group. Leukemia 10:836–843.[Web of Science][Medline]
16. Jaffe ES, Harris N, Stein H, World Health Vardiman J. (2001) Organisation Classification of Tumours: Tumours of the Hematopoietic and Lymphoid Tissues. (IARC Press, Lyon).
17. Cheson BD, Horning SJ, Coiffier B, et al. (1999) Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol 17:1244.
18. Nickenig C, Hoster E, Dreyling M, et al. (2006) Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hematologic toxicity compared with combined mitoxantrone chlorambucil and prednisone (MCP) in follicular and mantle cell lymphomas: results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group. Cancer 107:1014–1022.[CrossRef][Web of Science][Medline]
19. Whitehead J. (1992) The design and analysis of sequential clinical trials. Ellis Horwood Chichester.
20. Lenz G, Dreyling M, Schiegnitz E, et al. (2004) Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 22:4926–4933.
21. Mergenthaler HG, Bruhl P, Ehninger G, Heidemann E. (1987) Comparative in vitro toxicity of mitoxantrone and adriamycin in human granulocyte-macrophage progenitor cells. Cancer Chemother Pharmacol 20:8–12.[Web of Science][Medline]
22. Chow KU, Boehrer S, Bojunga J, et al. (2002) Induction of apoptosis by cladribine (2-CdA), gemcitabine and other chemotherapeutic drugs on CD34+/CD38+ and CD34+/CD38– hematopoietic progenitor cells: selective effects of doxorubicin and 2-CdA with protection of immature cells. Leuk Lymphoma 43:377–384.[Web of Science][Medline]
23. Bensinger W, Appelbaum F, Rowley S, et al. (1995) Factors that influence collection and engraftment of autologous peripheral-blood stem cells. J Clin Oncol 13:2547–2555.[Abstract]
24. Moskowitz CH, Glassman JR, Wuest D, et al. (1998) Factors affecting mobilization of peripheral blood progenitor cells in patients with lymphoma. Clin Cancer Res 4:311–316.
25. Morris CL, Siegel E, Barlogie B, et al. (2003) Mobilization of CD34+ cells in elderly patients (>/= 70 years) with multiple myeloma: influence of age, prior therapy, platelet count and mobilization regimen. Br J Haematol 120:413–423.[CrossRef][Web of Science][Medline]
26. Pavone V, Gaudio F, Guarini A, et al. (2002) Mobilization of peripheral blood stem cells with high-dose cyclophosphamide or the DHAP regimen plus G-CSF in non-Hodgkin's lymphoma. Bone Marrow Transplant 29:285–290.[CrossRef][Web of Science][Medline]
27. Clark RE and Brammer CG. (1998) Previous treatment predicts the efficiency of blood progenitor cell mobilisation: validation of a chemotherapy scoring system. Bone Marrow Transplant 22:859–863.[CrossRef][Web of Science][Medline]
28. McQuaker IG, Haynes AP, Stainer C, et al. (1997) Stem cell mobilization in resistant or relapsed lymphoma: superior yield of progenitor cells following a salvage regimen comprising ifosphamide, etoposide and epirubicin compared to intermediate-dose cyclophosphamide. Br J Haematol 98:228–233.[CrossRef][Web of Science][Medline]
29. O'Connell N, Gardiner N, Duggan C, et al. (2001) Effective progenitor cell mobilization in lymphoproliferative disorders using ifosfamide, epirubicin and etoposide (IEV). Eur J Haematol Suppl 64:33–36.[Medline]
30. Olivieri A, Offidani M, Ciniero L, et al. (1995) DHAP regimen plus G-CSF as salvage therapy and priming for blood progenitor cell collection in patients with poor prognosis lymphoma. Bone Marrow Transplant 16:85–93.[Web of Science][Medline]
31. Dreger P, Marquardt P, Haferlach T, et al. (1993) Effective mobilisation of peripheral blood progenitor cells with ‘Dexa-BEAM’ and G-CSF: timing of harvesting and composition of the leukapheresis product. Br J Cancer 68:950–957.[Web of Science][Medline]
32. Stiff P, Gingrich R, Luger S, et al. (2000) A randomized phase 2 study of PBPC mobilization by stem cell factor and filgrastim in heavily pretreated patients with Hodgkin's disease or non-Hodgkin's lymphoma. Bone Marrow Transplant 26:471–481.[CrossRef][Web of Science][Medline]
33. Jantunen E, Kuittinen T, Nousiainen T. (2003) Is chemotherapy scoring useful to predict progenitor cell mobilisation in patients with non-Hodgkin's lymphoma? Bone Marrow Transplant 32:569–573.[CrossRef][Web of Science][Medline]
34. Lenz G, Dreyling M, Schiegnitz E, et al. (2004) Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma: results of a prospective, randomized trial of the German Low-Grade Lymphoma Study Group. Blood 104:2667–2674.
35. Deconinck E, Foussard C, Milpied N, et al. (2005) 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 105:3817–3823.
36. Sebban C, Blanger C, Brousse N, et al. (2003) Comparison of CHVP + interferon with CHOP followed by autologous stem cell transplantation with a TBI conditioning regimen in untreated patients with high tumor burden follicular lymphoma: results of the randomized GELF94 trial (G.E.L.A. Study Group) [abstract]. Blood 102:11104.
37. Solal-Celigny P, Roy P, Colombat P, et al. (2004) Follicular lymphoma international prognostic index. Blood 104:1258–1265.
38. Buske C, Hoster E, Dreyling M, et al. (2006) The Follicular Lymphoma International Prognostic Index (FLIPI) separates high-risk from intermediate- or low-risk patients with advanced-stage follicular lymphoma treated front-line with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with respect to treatment outcome. Blood 108:1504–1508.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. Bendandi Aiming at a Curative Strategy for Follicular Lymphoma CA Cancer J Clin, September 1, 2008; 58(5): 305 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Ren, B. Korchin, G. Lahat, C. Wei, S. Bolshakov, T. Nguyen, W. Merritt, A. Dicker, A. Lazar, A. Sood, et al. Combined Vascular Endothelial Growth Factor Receptor/Epidermal Growth Factor Receptor Blockade with Chemotherapy for Treatment of Local, Uterine, and Metastatic Soft Tissue Sarcoma Clin. Cancer Res., September 1, 2008; 14(17): 5466 - 5475. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||