This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Velasquez, W. S. Articles by Fisher, R. I. Search for Related Content PubMed PubMed Citation Articles by Velasquez, W. S. Articles by Fisher, R. I. Social Bookmarking                            What's this?

Combination of Fludarabine and Mitoxantrone in Untreated Stages III and IV Low-Grade Lymphoma: S9501

William S. Velasquez, Danika Lew, Thomas M. Grogan, C. Harris Spiridonidis, Stanley P. Balcerzak, Shaker R. Dakhil, Thomas P. Miller, Keith S. Lanier, Robert A. Chapman, Richard I. Fisher

From the University of Texas Medical Branch, Galveston, TX; Southwest Oncology Group Statistical Center, Seattle, WA; University of Arizona Cancer Center, Tucson, AZ; Columbus Community Clinical Oncology Program, Ohio State University Health Center, Columbus, OH; Wichita Community Clinical Oncology Program, Wichita, KS; Columbia River Community Clinical Oncology Program, Portland, OR; Henry Ford Hospital, Detroit, MI; and University of Rochester School of Medicine, Rochester, NY.

Address reprint requests to Southwest Oncology Group (SWOG-9501), Operations Office, 14980 Omicron Dr, San Antonio, TX 77074; email: william.velasquez{at}usoncology.com.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To determine the efficacy of combination fludarabine and mitoxantrone (FN) in untreated stages III and IV low-grade lymphoma. The major end point was to estimate progression-free survival (PFS) in all eligible patients.

Patients and Methods: Seventy-eight eligible patients were registered. Chemotherapy courses were administered every 4 weeks with mitoxantrone 10 mg/m² on day 1 and fludarabine 25 mg/m² on days 1, 2, and 3 for a total of six to eight cycles. Pneumocystis carinii prophylaxis was required.

Results: Seventy-three patients (94%) attained an objective response. Complete remission was demonstrated in 34 patients (44%) and partial remission was demonstrated in 39 patients (50%). With a median follow-up time of 5.5 years, the median PFS was 32 months, with a 4-year PFS rate of 38%. Median survival has not been reached and 88% of all patients are alive at 4 years. The application of the International Prognostic Index and serologic staging showed significant differences in PFS in all risk groups, whereas overall survival was markedly worse for the highest-risk group in either prognostic model. Three prior Southwest Oncology Group trials using a regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone or a combination of prednisone, vincristine, methotrexate, cytarabine, cyclophosphamide, etoposide, nitrogen mustard, vincristine, procarbazine, and prednisone in similar patient populations demonstrated comparable clinical outcome, although the 4-year survival for FN was better. FN was well tolerated, but mild to severe reversible myelosuppression was noted. Other complications were rare.

Conclusion: FN is an effective, safe chemotherapy combination for patients with advanced-stage, low-grade lymphoma. Clinical outcomes were comparable to prior published data using anthracycline-based regimens.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
LOW-GRADE LYMPHOMAS, according to the Working Formulation classification, comprise a rather heterogeneous subgroup of lymphomas, all of which are associated with an indolent clinical course and median survival between 5 and 10 years.^1–3 Current Revised European-American Lymphoma and World Health Organization classifications have emphasized the diversity in the pathologic assessment; however, one of the most common pathologic subgroups in all classifications remains follicular lymphoma, a prototype of low-grade lymphoma.^4,5 At the time of diagnosis, most patients with low-grade lymphoma show extensive nodal involvement with or without bone marrow involvement and are classified as having Ann Arbor stages III and IV lymphoma. Typical initial treatment strategies of advanced stages of low-grade lymphoma have been based on the use of alkylating agents given either as a single drug or in combinations such as cyclophosphamide, vincristine, and prednisone or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). With these therapies, responses are common, but long-term remissions are noted in less than 20% to 30% of the treated population.^3,6

The Southwest Oncology Group (SWOG) has performed four consecutive trials in advanced-stage, low-grade lymphoma. The first three trials involved the use of an anthracycline-based regimen as described in prior publications.^6,7 Although the oldest trial (S7204) included a significant proportion of patients previously treated with radiation therapy, in the other two studies (S7426 and S7713), the number of previously treated patients was significantly smaller. The fourth clinical trial tested the combination of prednisone, vincristine, methotrexate, cytarabine, cyclophosphamide, etoposide, nitrogen mustard, vincristine, procarbazine, and prednisone (ProMACE-MOPP) in previously untreated patients.⁸ The analysis of these data shows the possibility of complete remission in approximately 57% to 63% of all patients, but overall survival plots demonstrate similar median survival ranging from 5.6 to 10 years. Although the use of interferon has been demonstrated by several investigators to increase progression-free or disease-free survival,^9,10 a SWOG trial using interferon for maintenance therapy failed to show this effect.⁸ Likewise, prior experience with other biologic therapies (bacille Calmette-Guérin) or levamisole did not improve duration of remission in complete responders.⁶

More recently, the efficacy of a newer drug combination has been reported by McLaughlin et al^11,12 for patients with relapsing low-grade lymphoma. The use of fludarabine, mitoxantrone, and dexamethasone (FND) induced a response rate of 94%, with a 46% complete remission rate that lasted a median of 21 months.¹² Although FND, in general, was well tolerated, a significant proportion of patients developed opportunistic infections, which included Pneumocystis carinii, herpes zoster, and mycobacterial infections. The potent antilymphocytic activity related to fludarabine, particularly for T cells, has been incriminated for this effect. Similar toxicities have been reported in fludarabine-treated patients with chronic lymphocytic leukemia; in this setting, the addition of corticosteroids increased the rate of opportunistic infection without additional significant antitumor effect.^13,14

In 1994, the SWOG Lymphoma Committee decided to test the fludarabine and mitoxantrone (FN) combination in previously untreated patients with advanced-stage, low-grade lymphoma. Dexamethasone was excluded to minimize the possibility of opportunistic infection. This phase II trial was designed to ascertain efficacy and toxicities of this combination and to determine whether the regimen was promising with respect to progression-free survival and overall survival.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
The protocol was designed and became available for enrollment in early 1995 for adult patients with stage III and IV low-grade lymphoma according to the Working Formulation classification.¹ Patients with mantle-cell lymphoma were excluded from this trial. All patients had to have evidence of measurable disease at the time of registration and to have signed a consent form from the local institutional review board. Other eligibility criteria included performance status of 0 to 2 by the SWOG criteria; normal hematologic, hepatic, and renal function testing; and a negative history for cardiac events and hepatitis. Patients with human immunodeficiency virus infection were also excluded from enrollment. All patients were staged by routine physical examination, computed tomography (CT) scans, and bone marrow aspiration and biopsies. Radiologic testing was repeated after two cycles of chemotherapy and at the end of treatment. Bone marrow biopsy was also repeated in responding patients if prior biopsy was positive. Subsequent CT scans were repeated every 6 months or at any time if signs of recurrence were noted. No attempt was made to obtain B-cell leukemia 2 (BCL₂) status in marrow or in blood. However, serum levels of lactic dehydrogenase and beta₂-microglobulin (ß₂-microglobulin) were measured before treatment.

Treatment Plan
The FN chemotherapy scheme administration consisted of mitoxantrone 10 mg/m² given as rapid intravenous infusion on day 1 and fludarabine 25 mg/m² administered by short intravenous infusion on days 1 to 3. The combination of trimethoperin-sulfa was administered once a day for Pneumocystis infection prophylaxis for the duration of the chemotherapy. Cycles were repeated every 28 days for a maximum of eight cycles. Complete blood cell counts and liver function tests were repeated before chemotherapy and should have demonstrated recovery from myelosuppression with absolute granulocyte count greater than 1,500/µL and platelet count greater than 100,000/µL. Treatments were delayed up to 2 weeks in cases of lower blood count levels, and both drugs were decreased by 25% if myelosuppression was persistent after 6 weeks. Adjustment to the doses was made for nonhematologic grade 3 or 4 toxicities with a dose reduction of 25%; in addition, the same degree of reduction was used when indicated for renal dysfunction (serum creatinine more than twice the normal limits) for fludarabine. For mitoxantrone, a reduction of 50% was applied for patients with serum bilirubin elevation greater than twice the normal value when hyperbilirubinemia was related to lymphoma involvement; subsequently, dosage was increased if levels of bilirubin improved. In cases of biliary duct obstruction by a tumor mass, placement of a biliary drainage shunt was recommended before initiation of therapy. Patients requiring more than two dose reductions were removed from protocol treatment.

Response Definition
Complete response was defined as absence of abnormalities in subsequent physical examinations and in the radiologic testing done by CT scans. Negative bone marrow biopsy was required if prior biopsy was indicative of involvement. Partial response was defined as a decrease by 50% in the sum of the products of perpendicular diameters of all measurable lesions, without evidence of the appearance of new lesions or persistent marrow involvement if radiologic testing became negative. Remission duration must last a minimum of 4 weeks. Any patient not achieving either a partial or a complete response was considered a nonresponder.

Statistical Considerations
The study was designed to accrue 80 eligible patients. Progression-free survival (PFS) and overall survival (OS) were calculated from the date of registration until patient death (OS) or date of registration until disease progression or patient death (PFS). OS and PFS were estimated by the Kaplan and Meier method¹⁵ on the basis of all eligible patients. Given complete follow-up, 80 patients would be sufficient to estimate the 2-year PFS to within at worst ± 11% (95% confidence interval [CI]). Eighty patients would also be sufficient to estimate the response and toxicity rates to within ± 11% (95% CI). Any adverse event occurring with at least 5% probability is likely to be seen at least once (98% chance). Analysis of the prognostic factor for PFS and OS was performed by the two-sided log-rank test comparing patient subgroups according to the International Prognostic Index,¹⁶ and by the serologic prognostic model reported by Swan et al¹⁷ using the dichotomy of normal or elevated lactate dehydrogenase (LDH) and different levels of ß₂-microglobulin using the cutoff level of 3 mg/L.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
A total of 92 patients were registered onto this study; however, low-grade lymphoma was not confirmed in 12 patients, including one patient with chronic lymphocytic leukemia who had an absolute lymphocyte count greater than 5,000/µL. Two additional patients had a history of cardiac disease. The clinical characteristics for the remaining 78 eligible patients and the univariate analysis of each clinical subgroup are shown in Table 1. As expected, most patients had stage IV disease and had a follicular lymphoma pattern either as small cleaved cell or mixed cell. Elevated serum LDH was found in 22% of patients. The median serum level for ß₂-microglobulin was 2.3 mg/L in the 77 eligible patients who had a pretreatment value.

With a median follow-up time of 5.5 years, a total of 50 patients have experienced disease progression, and two additional patients died without progression. The median PFS was 32 months; the calculated 2-year PFS rate was 60% (95% CI, 49% to 71%) and the calculated 4-year PFS rate is 38% (95% CI, 27% to 49%; Fig 1). Several other treatments were given at the time of progression, including chlorambucil, CHOP, and bone marrow or stem-cell transplantation. A total of 19 deaths have occurred, and the OS curve is 94% (95% CI, 88% to 99%) at 2 years and 88% (95% CI, 81% to 95%) at 4 years, with no clear plateau in either PFS or overall survival curves (Fig 2). In the Discussion, we review these results compared with the PFS and OS observed in three other prior SWOG trials.

View larger version (10K): [in this window] [in a new window]   Fig 1. Progression-free survival for fludarabine and mitoxantrone.

View larger version (10K): [in this window] [in a new window]   Fig 2. Overall survival for fludarabine and mitoxantrone.

The application of the IPI in our patient population showed a significant difference for PFS in the three subgroups: patients with low (IPI 0 to 1), low-intermediate (IPI 2), and high-intermediate (IPI 3 to 4) achieved 4-year PFS rates of 51%, 34%, and 13%, respectively (Table 2; P = < .01 for IPI 0 to 1 v IPI > 1; Fig 3). OS was similar for low and intermediate groups (97% and 96%) but was significantly lower for the high-intermediate group (60%). Only two patients corresponded to high-risk IPI, and both patients experienced disease progression within a few months after FN. Likewise, the univariate prognostic factor analysis demonstrated the significant impact of serum LDH and ß₂-microglobulin levels in prognosis, particularly for PFS (Table 1). When the two values were combined using the dichotomy of normal versus increased levels for LDH and the cutoff of 3 mg/L for ß₂-microglobulin level, three subgroups of patients were identified. Patients with low-risk serologic staging defined by normal LDH level and low ß₂-microglobulin level (< 3 mg/L) had a 4-year PFS rate of 57% compared with those patients in the high-risk group identified by the elevation of both serologic parameters of LDH and serum ß₂-microglobulin 3 mg/L with PFS of 0%, whereas the intermediate group with either elevated LDH or ß₂-microglobulin level showed a PFS of 16% at 4 years (P < .01; Fig 4). However, the 4-year OS rate was similar in the low and intermediate groups (96% and 84%, respectively) but significantly worse for the high-risk group (70%; P = .03; Table 2).

View larger version (12K): [in this window] [in a new window]   Fig 3. Progression-free survival according to International Prognostic Index (IPI).

View larger version (15K): [in this window] [in a new window]   Fig 4. Progression-free survival for fludarabine and mitoxantrone according to serologic staging. LDH, lactate dehydrogenase; B2, beta2-microglobulin.

Grade 3 lymphopenia (with lymphocyte counts between 500 and 900/µL) was noted in two patients. A total of 18 patients developed fever that was mostly associated with neutropenia, but 10 patients had a defined infection process, including a single catheter-related episode. Herpetic zoster infection was observed in three patients who had received four to eight cycles of chemotherapy. There were no treatment-related deaths during the administration of FN.

A total of six patients were removed from the protocol by the treating physician because of the toxicities encountered.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The initial therapeutic options for patients with advanced-stage, low-grade lymphoma can vary from observation to oral single-agent therapy or intravenous drug combination, without much impact on OS. Although responses tend to be higher for combination chemotherapy, the overall prognosis remains unchanged for any treatment, with median survival of 7 to 10 years. Prior SWOG trials of anthracycline-based regimens have been reviewed by Dana et al,⁶ who has shown long-term results to be similar to other, less aggressive therapies, with a median survival of 6.9 years in 893 analyzed patients. The oldest of these studies (S7204) included several patients who had previously received radiation therapy, whereas with the newer studies, the proportion of such patients was smaller. However, the most recent SWOG published trial (S8809) using ProMACE-MOPP with or without interferon did not allow any prior therapy.⁸ This study included six to eight cycles of chemotherapy with subsequent random assignment of responding patients to receive interferon or not. The objective response rate was 83% and complete response was obtained in 47% of all patients. The median PFS was similar between interferon-treated patients (4.1 years) and the control group (3.2 years).

In recent years, the purine analog compounds, particularly fludarabine, were found to have marked antitumor efficacy in low-grade lymphomas.^18,19 In 1994, McLaughlin et al^11,12 initiated a phase I and subsequent phase II trial of FND. In relapsed low-grade lymphoma, this combination was effective, inducing a response rate of 94% in 51 treated patients.¹² The median failure-free survival time was more than 14 months, and the drug combination was well tolerated. However, the main toxicities of this combination were myelosuppression and evidence of opportunistic infection. Herpes zoster infection (six episodes), P carinii infection (six episodes), and a single mycobacterial were reported in the 51 treated patients. The most plausible explanation of this high frequency of opportunistic infection was the T-lymphocyte depletion produced by fludarabine and worsened by the use of corticosteroids at higher doses. Thus in late 1994, the Lymphoma Committee at SWOG decided to try this combination in previously untreated patients, and corticosteroids were eliminated to reduce the opportunistic infection frequency. In our clinical trial, this new combination of fludarabine and mitoxantrone was effective in most patients, with an overall response rate of 94%. Progression-free survival of 38% at 4 years was noted, without a clear plateau in the Kaplan and Meier plot. Results for PFS from prior SWOG trials using CHOP (S7426 and S7713) or ProMACE-MOPP (S8809), were reviewed (Fig 5). Although this comparison can be misleading because it relates to patients treated several years ago with potential differences in staging methodologies, diagnosis, and criteria for response, the fact remains that patients treated with FN experienced outcomes similar to those of patients primarily treated with CHOP or ProMACE-MOPP with or without interferon. The 4-year OS rate for FN was estimated to be 88%. However, we suspect that this apparent improvement compared with the previous trials (Fig 6) is due to improved salvage therapy currently available because the PFS for the study was comparable with respect to earlier SWOG studies and other published trials.

View larger version (16K): [in this window] [in a new window]   Fig 5. Progression-free survival in Southwest Oncology Group trials in low-grade lymphoma. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; FN, fludarabine and mitoxantrone; ProMACE-MOPP, prednisone, vincristine, methotrexate, cytarabine, cyclophosphamide, etoposide, nitrogen mustard, vincristine, procarbazine, and prednisone.

View larger version (16K): [in this window] [in a new window]   Fig 6. Overall survival in Southwest Oncology Group trials in low-grade lymphoma. CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; FN, fludarabine and mitoxantrone; ProMACE-MOPP, prednisone, vincristine, methotrexate, cytarabine, cyclophosphamide, etoposide, nitrogen mustard, vincristine, procarbazine, and prednisone.

We also have confirmed the previously reported prognostic value of the IPI score for the determination of PFS and OS in our patient population.^3,20 In our study, given the limitations of performance status of up to 2 and the fact that our patients had advanced-stage disease, it is not unexpected that only two patients fall in the high-risk category. Nevertheless, a clear demarcation in prognosis was found between patients with low-risk factor (IPI 0 to 1) and the rest of the population. Likewise, we demonstrated the significant role of the serologic prognostic model on the basis of serum levels of LDH and ß₂-microglobulin previously reported in intermediate-grade lymphoma.¹⁷ One can postulate that serum LDH and serum ß₂-microglobulin could be related to malignant cell proliferation and tumor burden, respectively, which would valuable biologic information that would enable chemotherapy to be tailored to individual patients.

Other groups have also initiated or completed trials using fludarabine alone or in drug combinations as initial therapy for low-grade lymphoma.^21–25 Researchers at M.D. Anderson Cancer Center (Houston, TX) used FND in combination with interferon and compared it with alternating triple chemotherapy combinations (ATT) and interferon as front-line therapy for indolent lymphoma. In a recent publication, Tsimberidou et al²¹ reported the results of this trial in stage IV patients. The comparison favored ATT in terms of failure-free survival (50% for ATT plus interferon and 41% for FND plus interferon at 5 years), although survival was similar in both arms. However, the ATT and interferon arm implementation was complicated (only 75% of patients completed 75% of the assigned treatment courses) and associated with severe myeloid toxicities; among the 69 ATT-treated patients, two patients died from treatment complications and a third patient developed acute leukemia after treatment. For the FND and interferon arm, two patients developed P carinii infection and one toxic death occurred among the 73 treated patients. The 5-year failure-free survival rate for FND and interferon (41%) was comparable to PFS for FN (38% at 4 years for stages III and IV).

Additional encouraging data demonstrate that BCL₂ became negative by polymerase chain reaction analysis in a proportion of the follicular lymphoma patients.²⁶ However, no data in BCL₂ overexpression were obtained in our patient population, so a direct comparison for these data is not possible. Coiffier et al²³ also reported a comparison between fludarabine alone versus a combination of cyclophosphamide, doxorubicin, teniposide, and prednisolone plus interferon in high-risk follicular lymphoma in older patients; as a single drug, fludarabine showed inferior responses and shorter failure-free survival and OS, but it was better tolerated, with a lower degree of severe neutropenia (5% compared with 26% for the combination treatment). Another trial of fludarabine versus cyclophosphamide, vincristine, and prednisone by Hagenbeek et al²⁴ has been published in abstract form and shows better responses and better time to treatment failure for fludarabine-treated patients. A phase I trial of a combination of fludarabine and cyclophosphamide was designed by Hochster et al²⁷ and demonstrated a high response rate; however, Lazzarino et al²⁸ also found slow granulocytic and platelet count recovery in 40% of the courses of a similar combination and a 36% discontinuation rate because of persistent myelosuppression in 25 previously treated patients.

Other current protocols are also investigating the addition of monoclonal antibodies to standard chemotherapy regimens for the therapy of untreated low-grade lymphomas.^22,29,30 These combination treatments could lead to prolongation of remission because the antitumor activity of monoclonal antibodies is based in different mechanisms. In this regard, SWOG recently completed two phase II trials using either rituximab or an immunoconjugate as maintenance therapy after CHOP chemotherapy. Alternatively, Horning et al³¹ conducted an investigational trial in which high-dose chemotherapy yielded encouraging preliminary results in a young patient population.

	NOTES

 
Supported in part by the following Public Health Service Cooperative Agreement grants awarded by the National Cancer Institute, United States Department of Health and Human Services: CA38926, CA32102, CA13612, CA35261, CA04920, CA35431, CA45377, CA58416, CA46282, CA35119, CA96429, CA12644, CA45450, CA04919, CA42777, CA27057, CA58686, CA45560, CA22433, CA76462, CA37981, CA35178, CA35176, CA12213, CA20319, CA63850, CA52654, CA58415, CA35192, CA42028, CA35281, CA46136, and CA58658.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. The Non-Hodgkin’s Lymphoma Pathologic Classification Project: National Cancer Institute sponsored study of classification of non-Hodgkin’s lymphomas summary and description for a working formulation for clinical usage. Cancer 49:2112–2135, 1982[CrossRef][Medline]

2. Horning SJ: Natural history and therapy for the indolent non-Hodgkin’s lymphomas. Semin Oncol 20:75–88, 1993 (suppl)[Medline]

3. Decandin D, Lepage E, Brousse N, et al: Low-grade stage III-IV follicular lymphoma: Multivariate analysis of prognostic factors in 484 patients—A study of the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 17:2499–2505, 1999[Abstract/Free Full Text]

4. Harris NL, Jaffee ES, Stein H, et al: A revised European-American Classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361–1392, 1994[Free Full Text]

5. Pileri SA, Milani M, Fraternali-Orcioni G, et al: From the R.E.A.L. Classification to the upcoming WHO scheme: A step toward universal categorization of lymphoma entities? Ann Oncol 9:607–612, 1998[Free Full Text]

6. Dana BW, Dahlberg S, Nathwani B, et al: Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy. J Clin Oncol 11:644–651, 1993[Abstract]

7. Jones SE, Grozea PN, Miller TP, et al: Chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone alone or with levamisole or with levamisole plus BCG for malignant lymphoma: A Southwest Oncology Group study. J Clin Oncol 3:1318–1324, 1985[Abstract/Free Full Text]

8. Fisher RI, Dana BW, LeBlanc M, et al: Interferon alpha consolidation after intensive chemotherapy did not prolong the progression-free survival of patients with low-grade non-Hodgkin’s lymphoma: Results of the Southwest Oncology Group randomized phase III study 8809. J Clin Oncol 18:2010–2016, 2000[Abstract/Free Full Text]

9. Smalley RV, Weller E, Hawkins MJ, et al: Final analysis of the ECOG I-COPA trial (E6484) in patients with non-Hodgkin’s lymphoma treated with interferon alfa (IFN-alpha 2a) plus an anthracycline-based induction regimen. Leukemia 15:1118–1122, 2001[CrossRef][Medline]

10. Arranz R, Garcia-Alfonso P, Sobrino P, et al: Role of interferon alfa-2b in the induction and maintenance treatment of low-grade non-Hodgkin’s lymphoma: Results from a prospective, multicenter trial with double randomization. J Clin Oncol 16:1538–1546, 1998[Abstract/Free Full Text]

11. McLaughlin P, Hagemeister FB, Swan F, et al: Phase I study of the combination of fludarabine, mitoxantrone, and dexamethasone in low-grade lymphoma. J Clin Oncol 12:575–579, 1994[Abstract]

12. McLaughlin P, Hagemeister FB, Romaguera JE, et al: Fludarabine, mitoxantrone, and dexamethasone: An effective new regimen for indolent lymphoma. J Clin Oncol 14:1262–1268, 1996[Abstract/Free Full Text]

13. Anaisse EJ, Kontoyiannis DP, O’Brien S, et al: Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med 129:559–566, 1998[Abstract/Free Full Text]

14. Keating MJ, Smith TL, Lerner S, et al: Prediction of prognosis following fludarabine used as secondary therapy for chronic lymphocytic leukemia. Leuk Lymphoma 37:71–85, 2000[Medline]

15. Kaplan ES, Meier P: Non-parametric estimation from incomplete observation. J Am Stat Assoc 53:457–480, 1958[CrossRef]

16. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project: A predictive model for aggressive non-Hodgkin’s lymphoma. N Engl J Med 329:987–994, 1993[Abstract/Free Full Text]

17. Swan F, Velasquez WS, Tucker S, et al: A new serologic staging system for large-cell lymphomas based on initial beta-2-microglobulin and lactate dehydrogenase levels. J Clin Oncol 7:1518–1527, 1989[Abstract]

18. Redman JR, Cabanillas F, Velasquez WS, et al: Phase II trial of fludarabine phosphate in lymphoma: An effective new agent in low-grade lymphoma. J Clin Oncol 10:790–794, 1992[Abstract/Free Full Text]

19. Hochster HS, Kim KM, Green MD, et al: Activity of fludarabine in previously treated non-Hodgkin’s low-grade lymphoma: Results of an Eastern Cooperative Oncology Group study. J Clin Oncol 10:28–32, 1992[Abstract]

20. Lopez-Guillermo A, Montserrat E, Bosch F, et al: Applicability of the International Index for aggressive lymphomas to patients with low-grade lymphoma. J Clin Oncol 12:1343–1348, 1994[Abstract]

21. Tsimberidou AM, McLaughlin P, Younes A, et al: Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma. Blood 100:4351–4357, 2002[Abstract/Free Full Text]

22. McLaughlin P, Hagemeister FB, Rodriquez MA, et al: Safety of fludarabine, mitoxantrone, and dexamethasone combined with rituximab in the treatment of stage IV indolent lymphoma. Semin Oncol 27:37–41, 2000 (suppl)[Medline]

23. Coiffier B, Neidhardt-Berard EM, Tilly H, et al: Fludarabine alone compared to CHVP plus interferon in elderly patients with follicular lymphoma and adverse prognostic parameters: A GELA study—Groupe d’Etudes des Lymphomes l’Adulte. Ann Oncol 10:1191–1197, 1999[Abstract/Free Full Text]

24. Hagenbeek A, Eghbali H, Monfardini S, et al: Fludarabine versus conventional CVP chemotherapy in newly diagnosed patients with stages III and IV low-grade malignant non-Hodgkin’s lymphoma: Preliminary results from a prospective, randomized phase III clinical trial in 381 patients—American Society of Hematology meeting. Blood 92:315a, 1998 (abstr 1294)

25. Zinzani PL, Magagnoli M, Bendandi M, et al: Efficacy of fludarabine and mitoxantrone (FN) combination regimen in untreated indolent non-Hodgkin’s lymphomas. Ann Oncol 11:363–365, 2000[Abstract/Free Full Text]

26. Lopez-Guillermo A, Cabanillas F, McLaughlin P, et al: The clinical significance of molecular response in indolent follicular lymphoma. Blood 91:2955–2960, 1998[Abstract/Free Full Text]

27. Hochster HS, Oken MM, Winter JN, et al: Phase I study of fludarabine plus cyclophosphamide in patients with previously untreated low-grade lymphoma: Results and long-term follow-up—A report from the Eastern Cooperative Oncology Group. J Clin Oncol 18:987–994, 2000[Abstract/Free Full Text]

28. Lazzarino M, Orlandi E, Montillo M, et al: Fludarabine, cyclophosphamide, and dexamethasone (FluCyD) combination is effective in pretreated low-grade non-Hodgkin’s lymphoma. Ann Oncol 10:59–64, 1999[Abstract/Free Full Text]

29. Czuczman MS, Grillo-Lopez AJ, White CA, et al: Treatment of patients with low-grade B-cell lymphoma with the combination of chimeric anti-CD20 monoclonal antibody and CHOP chemotherapy. J Clin Oncol 17:268–276, 1999[Abstract/Free Full Text]

30. Longo DL, Duffey PL, Gribben JG, et al: Combination chemotherapy followed by an immunotoxin (anti B4-blocked ricin) in patients with indolent lymphoma: Results of a phase II study. Cancer J 6:146–150, 2000[Medline]

31. Horning SJ, Negrin RS, Hoppe RT, et al: High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: Results of a phase II clinical trial. Blood 97:404–409, 2001[Abstract/Free Full Text]

Submitted September 9, 2002; accepted February 24, 2003.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				J. G. Gribben How I treat indolent lymphoma Blood, June 1, 2007; 109(11): 4617 - 4626. [Abstract] [Full Text] [PDF]

				R. H. Shanks, D. A. Rizzieri, J. L. Flowers, O. M. Colvin, and D. J. Adams Preclinical Evaluation of Gemcitabine Combination Regimens for Application in Acute Myeloid Leukemia Clin. Cancer Res., June 1, 2005; 11(11): 4225 - 4233. [Abstract] [Full Text] [PDF]

				C. Foussard, P. Colombat, H. Maisonneuve, C. Berthou, R. Gressin, M.-C. Rousselet, P. Rachieru, B. Pignon, B. Mahe, C. Ghandour, et al. Long-term follow-up of a randomized trial of fludarabine-mitoxantrone, compared with cyclophosphamide, doxorubicin, vindesine, prednisone (CHVP), as first-line treatment of elderly patients with advanced, low-grade non-Hodgkin's lymphoma before the era of monoclonal antibodies Ann. Onc., March 1, 2005; 16(3): 466 - 472. [Abstract] [Full Text] [PDF]

				R. Marcus, K. Imrie, A. Belch, D. Cunningham, E. Flores, J. Catalano, P. Solal-Celigny, F. Offner, J. Walewski, J. Raposo, et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma Blood, February 15, 2005; 105(4): 1417 - 1423. [Abstract] [Full Text] [PDF]

				F. Hagemeister, F. Cabanillas, M. Coleman, S. A. Gregory, and P. L. Zinzani The Role of Mitoxantrone in the Treatment of Indolent Lymphomas Oncologist, February 1, 2005; 10(2): 150 - 159. [Abstract] [Full Text] [PDF]

				J. M. Vose, P. J. Bierman, C. Enke, J. Hankins, G. Bociek, J. C. Lynch, and J. O. Armitage Phase I Trial of Iodine-131 Tositumomab With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Relapsed Non-Hodgkin's Lymphoma J. Clin. Oncol., January 20, 2005; 23(3): 461 - 467. [Abstract] [Full Text] [PDF]

				P. L. Zinzani, A. Pulsoni, A. Perrotti, S. Soverini, F. Zaja, A. De Renzo, S. Storti, V. M. Lauta, L. Guardigni, P. Gentilini, et al. Fludarabine Plus Mitoxantrone With and Without Rituximab Versus CHOP With and Without Rituximab As Front-Line Treatment for Patients With Follicular Lymphoma J. Clin. Oncol., July 1, 2004; 22(13): 2654 - 2661. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Velasquez, W. S. Articles by Fisher, R. I. Search for Related Content PubMed PubMed Citation Articles by Velasquez, W. S. Articles by Fisher, R. I. Social Bookmarking                            What's this?