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Phase III Intergroup Study of Fludarabine Phosphate Compared With Cyclophosphamide, Vincristine, and Prednisone Chemotherapy in Newly Diagnosed Patients With Stage III and IV Low-Grade Malignant Non-Hodgkin's Lymphoma

Anton Hagenbeek, Houchingue Eghbali, Silvio Monfardini, Umberto Vitolo, Peter J. Hoskin, Christiane de Wolf-Peeters, Ken MacLennan, Elvira Staab-Renner, Joachim Kalmus, Astrid Schott, Ivana Teodorovic, Anastassia Negrouk, Martine van Glabbeke, Robert Marcus

From the European Organisation for Research and Treatment of Cancer (EORTC) Lymphoma Group, the British National Lymphoma Investigation Group, and the Dutch-Belgian Working Party on Hemato-Oncology, Academic Medical Center Amsterdam, Amsterdam, the Netherlands; Institut Bergonie Cancer Center, Bordeaux, France; Ospedale Civile di Padova, Padova; S Giovanni Battista Hospital, Torino, Italy; Mount Vernon Hospital, Northwood; St James's University Hospital, Leeds; Addenbrooke's Hospital, Cambridge, United Kingdom; University of Leuven Medical Center, Leuven; EORTC Data Center, Brussels, Belgium; and Schering AG, Berlin, Germany.

Address reprint requests to Anton Hagenbeek, MD, PhD, Academic Medical Center, Department of Hematology (F4-224), PO Box 22660, 1100 DD Amsterdam, the Netherlands; e-mail: a.hagenbeek{at}amc.uva.nl

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To compare the efficacy and safety of fludarabine phosphate with cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (lg) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study.

PATIENTS AND METHODS: Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m² intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m² IV on day 1; vincristine, 1.4 mg/m² IV on day 1; and prednisone, 40 mg/m² orally on days 1 through 5 every 4 weeks).

RESULTS: Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients.

CONCLUSION: Newly diagnosed lgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in lgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL.

	INTRODUCTION

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Low-grade (lg) non-Hodgkin's lymphoma (NHL) is a group of B-cell malignancies that follow an indolent clinical course and are incurable with currently available treatment strategies. For patients presenting with stage III or IV malignant lgNHL, the overall median survival time is 6 to 10 years.^1,2 Because of the relapsing and remitting nature of the disease, patients typically go through several cycles of increasingly shorter responses and rapid relapses.

Initial remissions may be induced with single-agent chlorambucil. Combination chemotherapy, such as cyclophosphamide, vincristine, and prednisone (CVP); the addition of anthracyclines, as in combinations such as CVP plus doxorubicin; and chemotherapy followed by irradiation all increase remission rates but have little impact on progression-free survival.^3-6 Prolonged, relapse-free survival is seldom achieved. The addition of interferon alfa to combination chemotherapy has been shown to prolong the duration of remission in some series but does not consistently improve survival.^7,8 Interferon alfa may also have significant long-term toxicity. Recently, the addition of the monoclonal antibody rituximab to standard chemotherapy has been shown to increase response rates and progression-free survival, but its impact on overall survival (OS) is uncertain.⁹ The failure of any first-line regimens to influence long-term survival has led to the adoption of a watchful waiting (W/W) policy in low tumor burden or asymptomatic patients.¹⁰ Because there is some relationship between the duration of first and subsequent remissions and increasing the duration of the interval between successive treatments is a worthwhile goal, there is an obvious need to evaluate new regimens in the therapy of lgNHL.

Fludarabine phosphate (Fludara; Ben Venue Laboratories, Bedford, OH [Schering AG, Berlin, Germany, from 1994 onward]) is a purine analog that has been shown to achieve substantial response rates, alone or in combination, in patients with relapsed low-grade lymphoma.^11-14 It is generally well tolerated, with myelosuppression and related susceptibility to infection being the main complications associated with its use. In several phase II trials in previously untreated lgNHL patients, fludarabine phosphate achieved response rates of 65% to 84%, with complete response (CR) rates of 37% to 47%^15-17 and response durations of up to 15.6 months.¹⁷

There have been few randomized trials conducted to establish a possible role for fludarabine phosphate, compared with conventional therapy, in lgNHL as either first- or second-line therapy. The results of a large phase III study in patients with relapsed lgNHL demonstrated that, although the overall response (OR) rate was similar, progression-free survival and treatment-free survival were significantly longer with fludarabine phosphate than with CVP (progression-free survival: 11 v 9.1 months, respectively; P = .03; and treatment-free survival: 15 v 11 months, respectively; P = .02).¹⁸ In addition, patients who received fludarabine phosphate achieved significantly improved scores for social function but not for other scores in a quality-of-life survey. However, these improvements did not translate into a significant difference in OS between the treatment groups. The objective of the present phase III study (European Organisation for Research and Treatment of Cancer No. 20921) was to directly compare the safety and efficacy of fludarabine phosphate with conventional CVP in patients with previously untreated, stage III or IV lgNHL.

	PATIENTS AND METHODS

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A phase III, prospective, randomized controlled trial was conducted to directly compare the safety and efficacy of fludarabine phosphate versus conventional CVP in previously untreated patients with malignant lgNHL. The study was conducted at 60 study centers in nine countries participating in the European Organisation for Research and Treatment of Cancer Lymphoma Group and the British National Lymphoma Investigation and in accordance with the European Good Clinical Practice guidelines (July 1990) and the recommendations of the Declaration of Helsinki (Hong Kong Amendments 1989). The protocol met all requirements of the appropriate regulatory authorities, and all participants gave informed, written consent.

Patient Population
Patients ( 18 years of age) were eligible if they met the following criteria: previously untreated, malignant lgNHL conforming to groups A, B, or C of the International Working Formulation (WF)¹⁹; Ann Arbor stage III or IV disease, including nodal and Waldeyer's ring localizations; at least one measurable tumor mass; and WHO performance status of 0, 1, or 2. Commonly used exclusion criteria were applied.

Treatment Policy
Individual study centers agreed to treat all patients on the basis of either an immediate treatment (ITx) or a W/W approach. At centers adopting the ITx policy, therapy was initiated within 1 month of diagnosis and staging in the majority of patients. Conversely, in centers adopting the W/W policy, patients were restaged, randomly assigned, and subsequently treated when treatment was thought to be indicated. If no treatment was initiated within a year of diagnosis, a repeat lymph node biopsy was performed to confirm the original diagnosis of malignant lgNHL.

Treatment
Eligible patients were randomly assigned to receive either fludarabine phosphate (25 mg/m²/d intravenous [IV] on days 1 through 5, every 4 weeks for up to eight cycles) or CVP (cyclophosphamide 750 mg/m² IV on day 1, vincristine sulfate 1.2 mg/m² IV [2 mg maximum] on day 1, and prednisone or prednisolone 40 mg/m² orally on days 1 through 5, every 4 weeks for up to eight cycles). Random assignment was stratified by institution and by treatment policy. No prophylaxis with antibiotics, antifungal drugs, or antiviral drugs was prescribed.

Dose Modification and Discontinuation Criteria
In the event of grade 2 or 3 nonhematologic toxicity, the fludarabine phosphate dose in subsequent cycles was reduced to 20 or 15 mg/m²/d, respectively. In the event of mild hematologic toxicity (granulocytes = 1.5 to 2.5 x 10⁹/L, but normal platelet count), the dose of fludarabine phosphate was reduced to 20 mg/m²/d. In the event of moderate hematologic toxicity (granulocytes = 1.0 to 1.5 x 10⁹/L and/or platelet count = 50 to 100 x 10⁹/L), the fludarabine phosphate dose was reduced to 10 mg/m²/d. In the event of severe toxicity (granulocytes < 1.0 x 10⁹/L and/or platelet count < 50 x 10⁹/L), fludarabine phosphate was withheld for up to 2 weeks. If platelet or granulocyte counts did not recover within this period, fludarabine phosphate was discontinued. Adjustments in CVP chemotherapy were performed according to local guidelines.

Evaluations
Each patient underwent a full clinical examination before the initiation of therapy, before each cycle of therapy, and throughout the follow-up period. The following were evaluated at each visit: erythrocyte sedimentation rate, hemoglobin, platelets, leukocytes, bilirubin, alkaline phosphatase, gamma glutamyltransferase, ALT and AST, lactate dehydrogenase, blood urea nitrogen, and creatinine. To assess the extent of disease, remission status, and early signs of progression, computed tomography of the thorax and abdomen and bone marrow biopsy were performed at study entry, if indicated during the chemotherapy period, after the end of treatment, and, when appropriate, during the follow-up period.

Follow-up evaluations were performed every 2 months in the first year of follow-up, quarterly in the second year of follow-up, and every 4 months thereafter. All patients still in remission after 4 years entered an individual observation period from the fifth year onward. Patients showing progression or patients who had withdrawn from the study as a result of any other reason entered the observation period until death occurred. This subgroup included nonresponders and patients showing response to treatment but who later experienced progression, all patients who were later assessed as ineligible for the study, and all patients who refused treatment.

Outcomes
CR was defined as the disappearance of all disease-related symptoms and measurable lesions, including normalization of abnormal blood values, x-rays, and bone marrow, with no disease in residually enlarged lymph nodes on biopsy or cytology. Partial response was defined as a minimum reduction of 50% in the product of the largest perpendicular diameters in all measurable and assessable lesions and the disappearance of disease-related symptoms. Progressive disease was defined as a minimum increase of 25% in the size of one or more lesions during treatment or the occurrence of new lesions. OS and time to treatment failure (TTF) were calculated from the date of first treatment. Time to progression (TTP) was calculated from the date of first treatment to the date of evaluation of progression. Patients who had not experienced disease progression at the time of last follow-up were censored in this analysis. The same was done for patients who died from a cause other than lymphoma (seven patients in the CVP arm and 10 patients in the fludarabine arm). For toxicity, the standard WHO definitions were applied (grades 0 to 4).

Statistical Analyses
The intended sample size was calculated to detect a 15% difference in the 4-year progression rate. This was considered, by consensus among the participating investigators, to be the minimum clinically relevant improvement in outcome. Accordingly, with = .05 and ß = .2, a total of 163 patients was required in each treatment arm (total study sample of 326 patients), with planned accrual between April 1993 and January 1997.

Statistical analyses of categoric data were performed using Mantel-Haenszel ² tests. For comparison of responses, patients with progressive disease and for whom response was not assessable at the end of treatment (25 patients in the CVP arm and 19 patients in the fludarabine arm) were classified as having experienced treatment failure. Survival data were analyzed according to the Kaplan-Meier method²⁰ and compared using the log-rank test. For all efficacy analyses, comparison tests were intended to be stratified by treatment policy.

	RESULTS

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Patient Population
In total, between April 1993 and January 1997, 381 patients were randomly assigned to treatment; patient demographics and characteristics are listed in Table 1. Both groups were quite similar. The same was true comparing the W/W and ITx subgroups (data not shown). Patient disposition is shown in Figure 1. Of the 381 patients included in the intent-to-treat (ITT) analysis, 14 (4%) did not receive study medication, primarily because of protocol violation, and 77 (20%) were declared ineligible because of inappropriate histology on central pathology review (eg, chronic lymphocytic leukemia or mantle-cell lymphoma). Responses were calculated in the ITT population (194 fludarabine phosphate patients v 187 CVP patients).

View larger version (11K): [in this window] [in a new window]   Fig 1. Flow chart for disposition of patients. CVP, cyclophosphamide, vincristine, and prednisone; ITT, intent to treat.

View larger version (11K): [in this window] [in a new window]   Fig 2. Time to progression (intent-to-treat patients). CVP, cyclophosphamide, vincristine, and prednisone.

View larger version (11K): [in this window] [in a new window]   Fig 3. Overall survival (intent-to-treat patients). CVP, cyclophosphamide, vincristine, and prednisone.

In both treatment groups, discontinuations of treatment were mainly related to relapse or progression (fludarabine phosphate, n = 33; CVP, n = 38; Fig 1). Premature discontinuations as a result of toxicity occurred more frequently in the fludarabine phosphate group than in the CVP treatment group (fludarabine phosphate, n = 13; CVP, n = 1).

Adverse events. The majority of frequently reported adverse events in both treatment groups were of mild to moderate intensity. Relevant grades 3 and 4 nonhematologic events are listed in Table 3. Grades 3 and 4 hematologic adverse events were more common in the fludarabine arm compared with the CVP arm (grade 3 granulocytopenia, 15.5% v 6.0%; grade 3 thrombocytopenia, 6.1% v 0.6%; grade 3 leukocytopenia, 22.1% v 4.5%; grade 3 anemia, 3.2% v 2.9%; grade 4 granulocytopenia, 11.6% v 5.4%; grade 4 thrombocytopenia, 1.6% v 0.5%; grade 4 leukocytopenia, 5.1% v 1.7%; grade 4 anemia, 1.5% v 1.2%, respectively). The low incidence of severe infections was similar in both groups (Table 3).

	DISCUSSION

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In phase II studies, fludarabine phosphate has demonstrated significant efficacy in the primary treatment of NHL,^16,17 highlighting the need for a direct comparative study with alkylating-agent therapy. In the current, prospective, randomized phase III clinical trial, it was shown that fludarabine induced twice as many CRs compared with CVP (ie, 38.6% v 15.0%, respectively). It should be noted that the CVP regimen used in this study consisted of a relatively low dose of cyclophosphamide (750 mg/m² IV administered every 4 weeks). Applying oral cyclophosphamide in a dose of 300 mg/m² for 5 days as part of CVP administered every 3 weeks yields a CR rate of 45% and an OR rate of 79%.⁷ In additional studies, the CR rate after CVP was not different from the current study (ie, 15% CR rate after cyclophosphamide 1,000 mg/m² IV in CVP administered every 3 weeks²¹ and 10% CR rate after cyclophosphamide 750 mg/m² IV in CVP administered every 3 weeks⁹). OR rates in these last two studies were 79% and 56%, respectively.

The CR rate reported for fludarabine in this study is similar to the rate in a large-scale, phase III, randomized trial treating chemotherapy-sensitive, relapsed patients.¹⁸ However, as in many other comparative studies, no benefit with regard to TTP or TTF was achieved, and there was no increase in OS.

No firm conclusions can be drawn regarding the results reported when patients were analyzed according to recruitment at W/W or ITx centers because inconsistencies in treatment arose at several treatment centers, including unclear treatment timing and/or patients receiving treatment at W/W centers earlier than specified by the protocol.

The improved efficacy of fludarabine phosphate in inducing partial responses and CRs is counterbalanced by an increase in grades 3 and 4 complications, particularly hematologic events, which is in line with the known safety profile of this agent. This study highlights the importance of appropriate dose reduction in the event of myelosuppression because two deaths were a result of a failure to reduce the dose, as dictated by the study protocol. The incidence of severe infections was similar in the two treatment arms.

Recently published studies suggest that additional agents used in combination with fludarabine phosphate may prolong the duration of remission.¹⁵ There are also good scientific reasons why the addition of rituximab to fludarabine or fludarabine-containing combinations might prove beneficial, including sensitization of CD20 cell lines and the downregulation, by fludarabine, of the anticomplement antigen CD55, which increases the susceptibility of lymphoma cells to antibody-mediated cell lysis.²² These experimental predictions are now being borne out in clinical practice.²³ Preliminary results with fludarabine phosphate–based regimens, such as fludarabine phosphate, mitoxantrone, and rituximab, in previously untreated patients with lgNHL have demonstrated OR rates of 97% and CR rates of 45%.²⁴ Eradication of disease at the molecular level has been observed in some lgNHL patients who achieved CR in response to first-line fludarabine phosphate, mitoxantrone, and rituximab therapy,²⁵ which is a finding that is promising for effective intervention early in the course of the disease and for the ability to achieve durable remissions. Other promising regimens include fludarabine phosphate, cyclophosphamide, mitoxantrone, and rituximab^26,27 (OR rate, 83%; CR rate, 35%) and fludarabine phosphate, mitoxantrone, dexamethasone, and rituximab (OR rate, 94%; CR rate, 81%).²⁸ Regimens now under active investigation as first-line therapy include combinations of fludarabine phosphate with cyclophosphamide,^29-32 mitoxantrone,^31-33 doxorubicin,³⁴ rituximab,^23,26-28 Y⁹⁰-ibritumomab tiuxetan, and ¹³¹I-tositumomab.^35-37

This study demonstrates that fludarabine phosphate is a highly effective single agent in the first-line therapy of lgNHL. Randomized studies to evaluate the potential role of this agent in combination with other cytotoxic drugs and monoclonal antibodies and yielding an increase in the duration of remission in lgNHL are based on this initial finding.

	Appendix

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The following physicians and centers participated in this study: Dr Eghbali, Fondation Bergonié, Bordeaux, France; Dr Resegotti, Ospedale Le Molinette, Torino, Italy; Dr Monfardini, Ospedale Civile di Padova, Padua, Italy; Dr Hagenbeek, formerly at Dr Daniel den Hoed Cancer Center, Rotterdam, Amsterdam, the Netherlands; Dr Hoskin, Mount Vernon, Northwood, Great Britain; Dr Hancock, Weston Park Hospital, Sheffield, Great Britain; Dr Van Hoof, St Jan Ziekenhuis, Brugge, Belgium; Dr Gouveia, Hospital Dos Capuchos, Lisbon, Portugal; Dr Somers, Antonie van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Dr Thomas, University Hospital Gasthuisberg, Leuven, Belgium; Dr Cavalli, Ospedale San Giovanni, Bellinzona, Switzerland; Dr Kluin-Nelemans, Leiden University Medical Center, Leiden, the Netherlands; Dr Marcus, Addenbrooke's Hospital, Cambridge, Great Britain; Dr Bron, Institut Jules Bordet, Brussels, Belgium; Dr Carde, Institut Gustave-Roussy, Villejuif, France; Dr Carotenuto, Casa Sollievo della Sofferenza, S.G. Rotondo, Italy; Dr Cunningham, Royal Marsden Hospital, Sutton, Great Britain; Dr Schroyens, University Hospital Antwerp, Antwerp, Belgium; Dr van Marwijk Kooy, Sophia Ziekenhuis, Zwolle, the Netherlands; Dr Mansi, St George's Hospital, London, Great Britain; Dr Newland, Royal London Hospital, London, Great Britain; Dr Sonneveld, University Hospital Dijkzigt, Rotterdam, the Netherlands; Dr Walewski, M. Sklodowska-Curie Institut, Warsaw, Poland; Dr Watkins, Lister Hospital, Herts, Great Britain; Dr Ferrazzi, Ospedale Civile, Rovigo, Italy; Dr Muller, Streekziekenhuis Gooi-Noord, Blaricum, the Netherlands; Dr Quigley, Oldchurch Hospital, Romford, Great Britain; Dr Stableforth, Sandwell District Hospital, London, Great Britain; Dr Wijermans, Leyenburg Hospital, The Hague, the Netherlands; Dr Catovsky, Royal Marsden Hospital, London, Great Britain; Dr Raemaekers, University Hospital Nijmegen, Nijmegen, the Netherlands; Dr Rhodes, Countess of Chester Hospital, Chester, Great Britain; Dr Santini, Ospedale San Marino, Genova, Italy; Dr Schaafsma, Medisch Spectrum Twente, Enschede, the Netherlands; Dr Stahel, University Hospital Zurich, Zurich, Switzerland; Dr Van Aelst, Hartziekenhuis, Roeselare, Belgium; Dr Verhoef, University Hospital Gasthuisberg, Leuven, Belgium; Dr De Bock, General Hospital Middelheim, Antwerp, Belgium; Dr MacWhannell, New Cross Hospital, Wolverhampton, Great Britain; Dr Roozendaal, Onze Lieve Vrouwe Gasthuis Amsterdam, Amsterdam, the Netherlands; Dr van Imhoff, University Hospital Groningen, Groningen, the Netherlands; Dr van Oers, Academic Medical Center Amsterdam, Amsterdam, the Netherlands; Dr Harper, Guy's Hospital, London, Great Britain; Dr Huijgens, University Hospital Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Dr Johnson, Taunton & Somerset Hospital, Taunton, Great Britain; Dr Milligan, Heartlands Hospital, Birmingham, Great Britain; Dr Schouten, University Hospital Maastricht, Maastricht, the Netherlands; Dr Varet, Hopital Necker, Paris, France; Dr Verdonck, University Medical Center Utrecht, Utrecht, the Netherlands; Dr Martinelli, European Institut of Oncology, Milan, Italy; Dr Moffat, Royal Gwent Hospital, Gwent, Great Britain; Dr Woodcock, Southport & Formby Hospital, Southport, Great Britain; Dr Bernasconi, Policlinico San Matteo, Pavia, Italy; Dr Jan-Mohamed, Hillingdon Hospital, Uxbridge, Great Britain; Dr Keuning, St Joseph's Hospital, Veldhoven, the Netherlands; Dr Kramer, Meander Medical Center, Amersfoort, the Netherlands; Dr Marangolo, Ospedale Civile, Ravenna, Italy; Dr Montserrat, Hospital Clínic y Provincial, Barcelona, Spain; Dr Singer, Royal United Hospital, Bath, Great Britain; and Dr Tanguy, Centre François Baclesse, Caen, France.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Anton Hagenbeek Roche International (A); Schering AG (A) Roche International (A); Schering AG (A) Elvira Staab-Renner Schering AG; (N/R) Schering AG (A) Joachim Kalmus Schering AG; (N/R) Schering AG (A) Astrid Schott Schering AG; (N/R) Schering AG (A) Anastassia Negrouk Schering AG (C) Martine van Glabbeke Schering AG (C) Robert Marcus Schering AG (A) Schering AG (A) Schering AG (A)

Dollar Amonut Codes (A) < $10,000 (B) $10,000-$99,900 (C) $100,000 (N/R) Not Required

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Anton Hagenbeek, Joachim Kalmus, Martine van Glabbeke, Robert Marcus Financial support: Joachim Kalmus, Astrid Schott Administrative support: Elvira Staab-Renner, Joachim Kalmus, Anastassia Negrouk Provision of study materials or patients: Anton Hagenbeek, Houchingue Eghbali, Silvio Monfardini, Umberto Vitolo, Peter J. Hoskin, Robert Marcus Collection and assembly of data: Anton Hagenbeek, Peter J. Hoskin, Elvira Staab-Renner, Joachim Kalmus, Ivana Teodorovic, Anastassia Negrouk, Robert Marcus, Ken MacLennan, Christiane de Wolf-Peeters Data analysis and interpretation: Anton Hagenbeek, Joachim Kalmus, Astrid Schott, Ivana Teodorovic, Martine van Glabbeke, Robert Marcus Manuscript writing: Anton Hagenbeek, Robert Marcus Final approval of manuscript: Anton Hagenbeek, Houchingue Eghbali, Silvio Monfardini, Umberto Vitolo, Peter J. Hoskin, Joachim Kalmus, Astrid Schott, Ivana Teodorovic, Anastassia Negrouk, Martine van Glabbeke, Robert Marcus

 

	NOTES

 
Supported by Schering AG, Berlin, Germany.

Presented in part at the 43rd Annual Meeting of the American Society of Hematology, Orlando, FL, December 7-11, 2001.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted August 9, 2005; accepted January 24, 2006.

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