|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Department of Medicine, Divisions of Bone
Marrow Transplantation and Medical Oncology, Department of Radiation
Oncology, and Department of Health Research and Policy, Division of
Biostatistics, Stanford University Medical Center, Stanford, CA.
Advanced stage follicular small cleaved and mixed cell lymphoma is
characterized by relapse from remission and survival ranging from 6 to
12 years. Because young patients have the greatest compromise in
longevity, the efficacy and toxicity of high-dose radiochemotherapy and bone marrow transplantation after conventional chemotherapy was
evaluated in a prospective phase II clinical trial. Thirty-seven patients in a minimal disease state after conventional chemotherapy received fractionated total body irradiation and high-dose etoposide and cyclophosphamide, followed by purged autologous bone marrow. A
reference sample of 188 patients of similar age, stage, and histology
managed at this institution before 1988 was identified for comparison
of patient characteristics and outcomes. Compared with reference
patients, transplant recipients had a higher tumor burden at diagnosis.
With a median follow-up of 6.5 years, the estimated 10-year survival
after transplantation was 86%. There was a single lymphoma death
yielding a 10-year disease-specific survival of 97%. There were 2 early transplant-related deaths and 2 late acute leukemia deaths. Ten
patients relapsed, one with microscopic disease only. High tumor burden
at diagnosis and incomplete response to chemotherapy adversely
influenced survival in the reference but not in the transplanted
patients. The estimated risk of death of 14% and relapse of 30% at 10 years in our transplanted follicular lymphoma patients, the majority of
whom had high tumor burdens, compares favorably with our observations
in appropriately matched reference patients.
(Blood. 2001;97:404-409) Advanced-stage low-grade lymphoma is a relatively
indolent disorder with median survivals of 6 to 12 years.1
Features of the natural history include a high initial rate of response
to chemotherapy and radiotherapy, recurrence of disease, transformation to a more aggressive histology, and occasional spontaneous
regression.1-3 Historically, single and multiple drug
alkylating agent-based therapy, with or without doxorubicin, has been
widely used in primary treatment. Other options have included deferred
therapy in selected patients, purine analogues alone or in combination, and interferon as induction or adjuvant therapy.2,4-8 Most studies have failed to demonstrate a survival advantage over historical or conventional controls.
In the 1980s, data emerging from Europe and the United States suggested
improved outcomes in selected patients with recurrent non-Hodgkin
lymphoma treated with high-dose therapy and autologous bone marrow
transplantation (ABMT).9,10 In addition to chemotherapy, ABMT permitted the use of myeloablative doses of total body
irradiation. This feature is attractive because follicular lymphomas
are exquisitely sensitive to radiotherapy, with sustained remissions in
a subset of limited-stage patients treated with moderate-dose regional radiation. The development of techniques to ex vivo purge residual lymphoma from the bone marrow further encouraged research efforts in
ABMT.10 These facts provided the rationale to explore the efficacy and safety of high-dose therapy and ABMT in relapsed follicular lymphoma.11-13 Because a major principle of
dose effect is intrinsic chemosensitivity of the tumor and tumors
acquire drug resistance in response to chemotherapy, the optimal timing for high-dose therapy with curative intent should be primary
treatment. On this basis, we conducted a prospective phase II
trial of high-dose therapy and ABMT in patients with follicular
lymphoma in first partial or complete remission.
Patient selection and treatment protocol
The schema for the clinical trial is outlined in Figure
1. Whenever possible, a representative
lymph node biopsy specimen was obtained to establish a tumor marker for
the evaluation of residual disease. Patients initially received
conventional chemotherapy cytoreduction. The combination of
cyclophosphamide 400 mg/m2 orally 5 times a day,
vincristine 1.4 mg/m2 (maximum dose 2 mg)
intravenously, and prednisone 100 mg/m2 orally 5 times a
day (CVP) was the preferred regimen. Treatment was continued for 2 cycles beyond best response, based on physical examination, computed
tomography, residual lymphogram contrast, and bone marrow biopsy. In
some cases, treatment was initiated before referral and alternate
chemotherapy combinations were used. In other cases, an alternative
regimen was used after CVP because MD had not been attained. As
detailed in Figure 1, on achievement of MD, patients proceeded to
marrow harvest on recovery of the white blood count. However, because
of suboptimal yield in some early patients, subsequent harvests were
performed after a 60-day recovery period. The marrow was treated with a
panel of monoclonal antibodies directed against CD9, CD10, CD19, and
CD20 plus rabbit complement as previously described.14 The
preparatory regimen consisted of ten 120 cGy fractions of total body
irradiation, etoposide (VP16) 60 mg/kg, and cyclophosphamide 100 mg/kg.14
Reference population and tumor burden evaluation
Polymerase chain reaction analysis Polymerase chain reaction (PCR) amplification at the major breakpoint regions (MBR) and minor cluster region (mcr) of the bcl-2/IgH rearrangement of the t(14;18) translocation were performed as previously described.16 Diagnostic material (lymph node biopsy) or bone marrow aspirates (if histologically involved) were subjected to PCR analysis to determine a tumor marker for individual patients. Bone marrow samples were analyzed before and after purging and periodically for long-term follow-up.Follow-up Recommended follow-up for patients was every 2 months for the first year, every 3 months for the second year, every 4 months for the third and fourth years, every 6 months for the fifth year, and annually thereafter. Chest and abdominal radiographs were recommended with each visit, the latter as long as lymphography contrast remained. Computerized tomography of the abdomen and pelvis and bone marrow biopsy were recommended annually. As previously noted, bone marrow aspirates obtained at Stanford were analyzed for molecular evidence of disease.Evaluation and statistical methods OS and freedom from progression (FFP) were calculated from the day of marrow transplantation for study patients and from the date of diagnosis for the reference sample. For the calculation of disease-specific survival, deaths due to other causes (n = 4) were censored. For the endpoint failure-free survival (FFS), the earlier event of relapse or death in remission was considered as the date of failure. Survival was estimated by the method of Kaplan and Meier.17 The log-rank test was used to compare survival curves.18
From August 1988 to April 1994, 37 patients met the eligibility
criteria and proceeded to transplantation. Their characteristics are
described in Table 1. The median age was
37 years (range 26 to 49). Sixty-two percent were male. Marrow
involvement was present in 86%. Twelve patients had more than one
extranodal disease site. The median number of Ann Arbor disease sites
was 9, ranging from 3 to 13. Despite extensive disease, only one
patient was nonambulatory (ECOG performance status 2 or greater) at
diagnosis. All patients had one adverse risk factor and one had 4 risk
factors according to the International Prognostic Factors Index, but
the majority had low- or low-intermediate-risk disease with missing lactate dehydrogenase in 7 patients.13 By eligibility
criteria, none of our patients were older than 60 years and, thus, the
distribution of IPI scores cannot be compared with the
available literature.
As seen in Table 2, 73% of patients had
a high tumor burden according to the GELF criteria before study entry.
About one third of the study patients had bulky disease and 19% had 3 or more lymph node sites greater than 3 cm. The median time from diagnosis to transplantation was 10 months. A single patient was observed initially and treated on disease progression.
All 37 patients received CVP chemotherapy, exclusively for 6 to 12 cycles in 24 patients, and with other chemotherapy combinations in 13 patients. Other combinations included CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for 2 to 6 cycles in 6 patients, CMOPP (cyclophosphamide, vincristine, procarbazine, prednisone) for 7 cycles in one patient, CNOP (cyclophosphamide, mitoxantrone, vincristine, prednisone) for 3 to 6 cycles in 2 patients, and ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mustard, vincristine, procarbazine, prednisone) for 2 to 6 cycles in 4 patients. The response to treatment was judged to be complete (CR) if no residual disease was found on restaging, which included bilateral marrow biopsies, computed tomographic scans, and physical examination. Eight patients (22%) achieved a CR, whereas the remaining 29 patients met the criteria for MD as previously defined. In 9 patients, the evidence for complete remission was deemed equivocal (CRe), usually the result of continued radiographic abnormalities of uncertain significance. Additional information on the status of the bone marrow was obtained at harvest, when core biopsy specimens from 6 sites were examined microscopically. Although these data were not included in the official restaging, just 28% were scored as negative. The remainder had residual lymphoma (34%), lymphoid aggregates (25%), or were scored as suspicious (13%). During the course of the study, granulocyte- (G-CSF) and granulocyte-macrophage (GM-CSF)-stimulating factors were introduced into practice. Some patients participated in a published double-blind study of GM-CSF.19 The median time to absolute neutrophil recovery to 500/µL was 13 days and platelet recovery to greater than 20 000/µL was 29 days. The initial patient treated on the study did not receive a purged product. Two patients received a "boost" of unpurged cells at days 34 and 44 because of persistent pancytopenia. With the exception of 2 early deaths, all patients reconstituted successfully. The median number of hospital days was 26. Standard antimicrobial protocols for neutropenic patients and blood product transfusion were followed. The 2 early transplant-related deaths involved a 24-year-old woman with prolonged neutropenia and fungal endocarditis and a 28-year-old man who had an overwhelming Epstein-Barr-related lymphoproliferative disorder develop as published previously.20 With a follow-up period after transplant ranging from 4 to 12 years
(median 6.5), the OS was estimated at 92% at 5 years and 86% at 10 years (Figure 2A). Recurrent lymphoma was
associated with a single death. In addition to the 2 early deaths
described previously, 2 patients had acute myelogenous leukemia (AML)
develop at 23 and 69 months. The estimated disease-specific survival, which considers deaths due to other causes as censored observations, was 100% at 5 years and 97% at 10 years (Figure 2A). Ten patients relapsed after transplantation with lymph node involvement as the site
of first relapse in 9 cases. The remaining patient had microscopic
disease on a screening marrow biopsy at 3 years; however, the marrow
biopsy specimen was negative the following year and the patient has had
no further evidence of lymphoma in the 3 years since relapse. One
patient relapsed with follicular large cell lymphoma. Second-line
treatments were selected according to physician and patient preference.
At least 3 patients were successfully treated with the anti-CD20
antibody, rituximab. The estimated FFP at 5 and 10 years after
transplant was 76% and 70%, respectively (Figure 2B). FFS was
estimated at 70% at 5 years and 60% at 10 years (Figure 2B). The
majority of patients continuing in remission have been in compliance
with follow-up, although enthusiasm of both physicians and patients for
annual bone marrow biopsies waned after 5 to 8 years.
Figure 3A illustrates OS according to
response to conventional chemotherapy in the study population. No
difference between patients achieving a CR or CRe and those with a very
good partial response was seen. Similarly, as shown in Figure 3B,
survival differences between high and low tumor burden patients were
not apparent although only 10 patients had low tumor burden disease.
The t(14;18) PCR analysis was performed on 25 patients before and after in vitro purging. Ten (40%) patients were found to be positive. Of those 10 patients, 7 (70%) were converted to PCR-negative, whereas 3 remained persistently positive. Among reference patients, 52% were male, 70% had stage IV disease,
and 72% had FSC histology. Eighty-six percent of the cases that could
be scored according to the international prognostic factors index had
low or low-intermediate risk.13 The estimated FFP at 5 and
10 years were 52% and 30% for this reference sample and the OS at 5 and 10 years were 88% and 62% (Figure
4A). Tumor burden characteristics of the
study patients were compared with the reference patients as detailed in
Table 2. Seventy-three percent of transplant recipients had high tumor
burden disease compared with 49% of the reference sample, and
the latter proportion did not change over the interval from 1962 to 1988. FFP may be a misleading endpoint because of potential
differences in the methods and frequency of disease surveillance, and
significant differences in FFP may not translate into a survival
benefit. Therefore, survival was adopted as the major endpoint for
further analyses.
As shown in Figure 4B and in contrast to the transplanted patients, application of the GELF criteria stratified low and high tumor burden reference patients into prognostic subgroups: 92% versus 70% OS at 5 years, P = .0001. A potentially important difference between the transplanted and reference patients is the selection of the former on the basis of response to conventional chemotherapy. Among reference patients treated immediately after diagnosis, 74% achieved a CR or CRe compared with 49% of the study population. Response to induction chemotherapy was of prognostic significance in the reference population overall and in the subset of patients treated with CVP chemotherapy. OS at 10 years was 36% for patients with partial response compared with 59% for patients with CR or CRe after CVP (P = .03) (Figure 4C). As previously stated, 2 patients had AML develop at 23 and 69 months after transplantation. The former patient had normal marrow cytogenetics at 12 months and a complex karyotype on the diagnosis of AML with deletions of chromosomes 7 and 5. The latter patient had 6 prior cytogenetic analyses of the bone marrow performed. At 3 years, a clonal abnormality was noted that included a chromosome 7 deletion but this clone was not present on 3 subsequent samples. The malignant clone was not related to that seen earlier but did contain a chromosome 7 deletion as well as a 5q deletion.
Multiple investigators have reported long remissions with myeloablative therapy and ABMT relative to conventional chemotherapy, albeit with continued relapses.11-13 Whereas possible survival benefit has been suggested in these uncontrolled trials, this positive effect has not been demonstrated definitively.21 Freedman et al22 reported 89% OS and 63% disease-free survival without evident plateau at 3 years among 87 patients who underwent ABMT in first remission. Only 36% of patients achieved a CR with CHOP chemotherapy before transplantation in this series in which the high-dose regimen had consisted of cyclophosphamide and total body irradiation. These investigators determined that the presence of minimal residual disease in the reinfused marrow was the most significant prognostic factor for relapse among these patients, concordant with their observations among patients in second or subsequent remission.21-23 Although the number evaluated was small, more than half of our patients had no molecular evidence of lymphoma in the marrow before purging and just 3 had minimal residual disease after purging. Thus, no correlation could be made with outcome in the current series. Differences in these findings may relate to the purging technique, PCR methodology, or variation in cytoreductive therapy before transplantation. Description of the characteristics of our study population and comparison to results among like patients treated with conventional therapy is essential to the interpretation of outcomes. Thus, an important and unique aspect of the current report is the provision of outcome data among patients of similar age treated without transplantation at the same institution. Longer survival was recorded for transplant recipients relative to reference patients, particularly those with a high tumor burden. Proportionally more patients had high tumor burden among the transplant recipients. However, the study patients were selected on the basis of achieving MD with conventional chemotherapy and response to chemotherapy (CR or CRe versus PR) was highly prognostic in the reference population. In fact, the 59% 10-year OS among CR patients in the CVP-treated reference group was not significantly different (P = .074) from the 86% 10-year OS among the study patients. Although fewer transplanted patients achieved a CR or CRe relative to reference patients, this may be related to greater sophistication in diagnostic techniques and acumen over time rather than a reflection of chemosensitivity. These comparisons indicate that, among patients treated with conventional therapy, OS was influenced by tumor burden and response to therapy, whereas these variables had little or no influence in the transplanted population. The observation of a single death due to lymphoma in the study population is a remarkable finding given the duration of follow-up. However, the occurrence of 4 deaths unrelated to relapse is of concern. The early deaths were unusual and might not be expected with advances in transplantation such as the use of peripheral blood stem cells and G-CSF, both of which reduce the time to engraftment and regimen-related complications. Secondary MDS and AML, however, continue to be a major concern for long-term survivors of autologous transplantation.22 In a recent series of 552 autologous transplant recipients, the estimated incidence of myelodysplasia at 10 years was 19.8% although others have reported a lower incidence of this complication, which has been related to cumulative doses of conventional cytotoxic drugs, preparatory regimen, and dose of cells reinfused at transplantation.24-26 The major cause of failure in the current study was recurrent disease, which was estimated at 30% at 10 years. Although this observation compares very favorably with historical references, it also indicates the need for further improvement. The use of immunomodulatory and targeted therapies after transplantation when the patient is in a minimal residual disease state is an attractive strategy, although the suppressive effects of high-dose therapy on effector cells and antigen-presenting cells present potential obstacles to this approach.27-29 Enhancement of the preparatory regimen through the use of radioimmunoconjugates or rituximab combined with cytotoxic therapy or the use of rituximab as a means of in vivo purging represent other approaches.30,31 Allogeneic transplantation in follicular lymphoma has been associated with a lower relapse rate and anecdotal evidence of response to donor lymphocyte infusions, suggesting a graft-versus-lymphoma effect.32 Newer strategies incorporating nonmyeloablative preparatory regimens may provide this effect with less morbidity and mortality.33 The long natural history of follicular lymphoma requires mature follow-up of clinical trials such as ours. Even then, interpretation of data are subject to error because of potential bias in patient selection. Clinicians appreciate that the course of disease is highly variable and a subset of patients remains healthy, without symptoms and without treatment, at 10 or more years. The estimated probability of death of 14% and relapse of 30% at 10 years in our transplanted patients, the majority of whom had high tumor burden disease, is significantly lower than our reference sample. However, treatments with greater potential for serious early and late effects must be carefully scrutinized and ideally reserved for patients at greatest risk for disease-related morbidity and mortality. We conclude that further investigations of transplantation with the objectives of reducing toxicity and disease recurrence are warranted as are efforts to describe prognostic factors in follicular lymphoma patients.
Submitted July 20, 2000; accepted October 9, 2000.
Supported in part by National Institutes of Health grants CA 49605 and CA 34233.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Sandra J. Horning, 1000 Welch Rd, Suite 202, Palo Alto, CA 94304; e-mail: sandra.horning{at}stanford.edu.
1. Horning SJ. Natural history of and therapy for the indolent non-Hodgkin's lymphomas. Semin Oncol. 1993;20:75-88[Medline] [Order article via Infotrieve]. 2. Horning SJ, Rosenberg SA. The natural history of initially untreated low-grade non-Hodgkin's lymphomas. N Engl J Med. 1984;311:1471-1475[Abstract].
3.
Johnson PW, Rohatiner AZ, Whelan JS, et al.
Patterns of survival in patients with recurrent follicular lymphoma: a 20-year study from a single center.
J Clin Oncol.
1995;13:140-147
4.
McLaughlin P, Hagemeister FB, Romaguera JE, et al.
Fludarabine, mitoxantrone, and dexamethasone: an effective new regimen for indolent lymphoma.
J Clin Oncol.
1996;14:1262-1268 5. Solal-Céligny P, Lepage E, Brousse N, et al. Doxorubicin-containing regimen with or without interferon alfa-2b for advanced follicular lymphomas: final analysis of survival and toxicity in the Groupe d'Etude des Lymphomes Folliculaires 86 Trial. J Clin Oncol. 1998;16:2332-2338[Abstract].
6.
Price CG, Rohatiner AZ, Steward W, et al.
Interferon-alpha 2b in the treatment of follicular lymphoma: preliminary results of a trial in progress.
Ann Oncol.
1991;2:141-145 7. Smalley RV, Andersen JW, Hawkins MJ, et al. Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin's lymphoma. N Engl J Med. 1992;327:1336-1341[Abstract].
8.
Fisher RI, Dana BW, LeBlanc M, et al.
Interferon alfa consolidation after intensive chemotherapy does 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.
2000;18:2010-2016 9. Philip T, Armitage JO, Spitzer G, et al. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med. 1987;316:1493-1498[Abstract]. 10. Takvorian T, Canellos GP, Ritz J, et al. Prolonged disease-free survival after autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma with a poor prognosis. N Engl J Med. 1987;316:1499-1505[Abstract].
11.
Freedman AS, Ritz J, Neuberg D, et al.
Autologous bone marrow transplantation in 69 patients with a history of low-grade B-cell non-Hodgkin's lymphoma.
Blood.
1991;77:2524-2529
12.
Rohatiner AZ, Johnson PW, Price CG, et al.
Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma.
J Clin Oncol.
1994;12:1177-1184
13.
A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project.
N Engl J Med.
1993;329:987-994
14.
Horning SJ, Negrin RS, Chao JC, Long GD, Hoppe RT, Blume KG.
Fractionated total-body irradiation, etoposide, and cyclophosphamide plus autografting in Hodgkin's disease and non-Hodgkin's lymphoma.
J Clin Oncol.
1994;12:2552-2558
15.
Brice P, Bastion Y, Lepage E, et al.
Comparison in low-tumor-burden follicular lymphomas between an initial no-treatment policy, prednimustine, or interferon alfa: a randomized study from the Groupe d'Etude des Lymphomes Folliculaires. Groupe d'Etude des Lymphomes de l'Adulte.
J Clin Oncol.
1997;15:1110-1117
16.
Negrin RS, Pesando J.
Detection of tumor cells in purged bone marrow and peripheral-blood mononuclear cells by polymerase chain reaction amplification of bcl-2 translocations.
J Clin Oncol.
1994;12:1021-1027 17. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457[CrossRef]. 18. Peto R. Asymptotically efficient rank invariant test procedures. J R Stat Soc. 1972;135:185-206. 19. Advani R, Chao NJ, Horning SJ, et al. Granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjunct to autologous hemopoietic stem cell transplantation for lymphoma. Ann Intern Med. 1992;116:183-189. 20. Chao NJ, Berry GJ, Advani R, Horning SJ, Weiss LM, Blume KG. Epstein-Barr virus-associated lymphoproliferative disorder following autologous bone marrow transplantation for non-Hodgkin's lymphoma. Transplantation. 1993;55:1425-1428[Medline] [Order article via Infotrieve].
21.
Freedman AS, Neuberg D, Mauch P, et al.
Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma.
Blood.
1999;94:3325-3333
22.
Freedman AS, Gribben JG, Neuberg D, et al.
High-dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission.
Blood.
1996;88:2780-2786 23. Gribben JG, Freedman AS, Neuberg D, et al. Immunologic purging of marrow assessed by PCR before autologous bone marrow transplantation for B-cell lymphoma. N Engl J Med. 1991;325:1525-1533[Abstract].
24.
Friedberg JW, Neuberg D, Stone RM, et al.
Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin's lymphoma.
J Clin Oncol.
1999;17:3128-3135
25.
Stone RM, Neuberg D, Soiffer R, et al.
Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma.
J Clin Oncol.
1994;12:2535-2542
26.
Darrington DL, Vose JM, Anderson JR, et al.
Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies.
J Clin Oncol.
1994;12:2527-2534
27.
Nagler A, Ackerstein A, Or R, Naparstek E, Slavin S.
Immunotherapy with recombinant human interleukin-2 and recombinant interferon-alpha in lymphoma patients postautologous marrow or stem cell transplantation.
Blood.
1997;89:3951-3959 28. Davis TA, Hsu FJ, Caspar CB, et al. Idiotype vaccination following ABMT can stimulate specific anti-idiotype immune response in patients with B cell lymphoma [abstract]. Proc Am Soc Clin Oncol. 1999;18:3a. 29. Horwitz S, Negin R, Hu W, et al. Phase I-II feasibility trial of rituximab following high dose chemotherapy and autografting in B-cell non-Hodgkin's lymphoma [abstract]. Ann Oncol. 1999;10:75a. 30. Liu SY, Eary JF, Petersdorf SH, et al. Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin Oncol. 1998;16:3270-3278[Abstract]. 31. Flinn IW, O'Donnell P, Noga SJ, et al. In vivo purging with rituximab during stem cell transplantation for indolent lymphoma [abstract]. Blood. 1999;94:638a. 32. van Besien KW, Khouri IF, Giralt SA, et al. Allogeneic bone marrow transplantation for refractory and recurrent low-grade lymphoma: the case for aggressive management. J Clin Oncol. 1995;13:1096-1102[Abstract]. 33. McSweeney PA, Storb R. Mixed chimerism: preclinical studies and clinical applications. Biol Blood Marrow Transplant. 1999;5:192-203[CrossRef][Medline] [Order article via Infotrieve].
© 2001 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  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]
|
|
|
|
 |
|
 C. Sebban, P. Brice, R. Delarue, C. Haioun, B. Souleau, N. Mounier, N. Brousse, P. Feugier, H. Tilly, P. Solal-Celigny, et al. Impact of Rituximab and/or High-Dose Therapy With Autotransplant at Time of Relapse in Patients With Follicular Lymphoma: A GELA Study J. Clin. Oncol., July 20, 2008; 26(21): 3614 - 3620. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Smith, F. Jin, and I. Joshi Bortezomib Sensitizes Non Hodgkin's Lymphoma Cells to Apoptosis Induced by Antibodies to Tumor Necrosis Factor Related Apoptosis-Inducing Ligand (TRAIL) Receptors TRAIL-R1 and TRAIL-R2 Clin. Cancer Res., September 15, 2007; 13(18): 5528s - 5534s. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Gribben How I treat indolent lymphoma Blood, June 1, 2007; 109(11): 4617 - 4626. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Sebban, N. Mounier, N. Brousse, C. Belanger, P. Brice, C. Haioun, H. Tilly, P. Feugier, R. Bouabdallah, C. Doyen, et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA) Blood, October 15, 2006; 108(8): 2540 - 2544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-W. Kim, T. E. Tanimoto, N. Hirabayashi, S. Goto, M. Kami, S. Yoshioka, T. Uchida, K. Kishi, Y. Tanaka, A. Kohno, et al. Myeloablative allogeneic hematopoietic stem cell transplantation for non-Hodgkin lymphoma: a nationwide survey in Japan Blood, July 1, 2006; 108(1): 382 - 389. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Liu, L. Fayad, F. Cabanillas, F. B. Hagemeister, G. D. Ayers, M. Hess, J. Romaguera, M. A. Rodriguez, A. M. Tsimberidou, S. Verstovsek, et al. Improvement of Overall and Failure-Free Survival in Stage IV Follicular Lymphoma: 25 Years of Treatment Experience at The University of Texas M.D. Anderson Cancer Center J. Clin. Oncol., April 1, 2006; 24(10): 1582 - 1589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Hiddemann, M. Kneba, M. Dreyling, N. Schmitz, E. Lengfelder, R. Schmits, M. Reiser, B. Metzner, H. Harder, S. Hegewisch-Becker, et al. 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, December 1, 2005; 106(12): 3725 - 3732. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Nabhan Should We Transplant Indolent Lymphoma? J. Clin. Oncol., September 1, 2005; 23(25): 6263 - 6264. [Full Text] [PDF]
|
|
|
|
|
|
E. Deconinck, C. Foussard, N. Milpied, P. Bertrand, P. Michenet, P. Cornillet-LeFebvre, M. Escoffre-Barbe, H. Maisonneuve, V. Delwail, R. Gressin, et al. 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, May 15, 2005; 105(10): 3817 - 3823. [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]
|
|
|
|
|
|
G. Lenz, M. Dreyling, E. Schiegnitz, T. Haferlach, J. Hasford, M. Unterhalt, and W. Hiddemann 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., December 15, 2004; 22(24): 4926 - 4933. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. R. Smith, F. Jin, and I. Joshi Enhanced efficacy of therapy with antisense BCL-2 oligonucleotides plus anti-CD20 monoclonal antibody in scid mouse/human lymphoma xenografts Mol. Cancer Ther., December 1, 2004; 3(12): 1693 - 1699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Forstpointner, M. Dreyling, R. Repp, S. Hermann, A. Hanel, B. Metzner, C. Pott, F. Hartmann, F. Rothmann, R. Rohrberg, et al. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group Blood, November 15, 2004; 104(10): 3064 - 3071. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Brugger, J. Hirsch, F. Grunebach, R. Repp, P. Brossart, W. Vogel, H.-G. Kopp, M. G. Manz, M. Bitzer, G. Schlimok, et al. Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: a prospective, multicenter phase II study Ann. Onc., November 1, 2004; 15(11): 1691 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Lenz, M. Dreyling, E. Schiegnitz, R. Forstpointner, H. Wandt, M. Freund, G. Hess, L. Truemper, V. Diehl, M. Kropff, et al. 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, November 1, 2004; 104(9): 2667 - 2674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Bendandi, S. A. Pileri, and P. L. Zinzani Challenging paradigms in lymphoma treatment Ann. Onc., May 1, 2004; 15(5): 703 - 711. [Full Text] [PDF]
|
|
|
|
|
|
P. Corradini, M. Ladetto, F. Zallio, M. Astolfi, E. Rizzo, S. Sametti, A. Cuttica, R. Rosato, L. Farina, M. Boccadoro, et al. Long-Term Follow-Up of Indolent Lymphoma Patients Treated With High-Dose Sequential Chemotherapy and Autografting: Evidence That Durable Molecular and Clinical Remission Frequently Can Be Attained Only in Follicular Subtypes J. Clin. Oncol., April 15, 2004; 22(8): 1460 - 1468. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Izutsu, Y. Kanda, H. Ohno, H. Sao, H. Ogawa, Y. Miyazaki, K. Kawa, Y. Kodera, S. Kato, Y. Morishima, et al. Unrelated bone marrow transplantation for non-Hodgkin lymphoma: a study from the Japan Marrow Donor Program Blood, March 1, 2004; 103(5): 1955 - 1960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. van Besien, F. R. Loberiza Jr, R. Bajorunaite, J. O. Armitage, A. Bashey, L. J. Burns, C. O. Freytes, J. Gibson, M. M. Horowitz, D. J. Inwards, et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma Blood, November 15, 2003; 102(10): 3521 - 3529. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. A. Lister High-Dose Therapy for Follicular Lymphoma Revisited: Not If, but When? J. Clin. Oncol., November 1, 2003; 21(21): 3894 - 3896. [Full Text] [PDF]
|
|
|
|
|
|
H. C. Schouten, W. Qian, S. Kvaloy, A. Porcellini, H. Hagberg, H. E. Johnsen, J. K. Doorduijn, M. R. Sydes, and G. Kvalheim High-Dose Therapy Improves Progression-Free Survival and Survival in Relapsed Follicular Non-Hodgkin's Lymphoma: Results From the Randomized European CUP Trial J. Clin. Oncol., November 1, 2003; 21(21): 3918 - 3927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. K. Gopal, T. A. Gooley, D. G. Maloney, S. H. Petersdorf, J. F. Eary, J. G. Rajendran, S. A. Bush, L. D. Durack, J. Golden, P. J. Martin, et al. High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis Blood, October 1, 2003; 102(7): 2351 - 2357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. W. Press, J. M. Unger, R. M. Braziel, D. G. Maloney, T. P. Miller, M. LeBlanc, E. R. Gaynor, S. E. Rivkin, and R. I. Fisher A phase 2 trial of CHOP chemotherapy followed by tositumomab/iodine I 131 tositumomab for previously untreated follicular non-Hodgkin lymphoma: Southwest Oncology Group Protocol S9911 Blood, September 1, 2003; 102(5): 1606 - 1612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Velasquez, D. Lew, T. M. Grogan, C. H. Spiridonidis, S. P. Balcerzak, S. R. Dakhil, T. P. Miller, K. S. Lanier, R. A. Chapman, and R. I. Fisher Combination of Fludarabine and Mitoxantrone in Untreated Stages III and IV Low-Grade Lymphoma: S9501 J. Clin. Oncol., May 15, 2003; 21(10): 1996 - 2003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Hosing, R. M. Saliba, P. McLaughlin, B. Andersson, M. A. Rodriguez, L. Fayad, F. Cabanillas, R. E. Champlin, and I. F. Khouri Long-term results favor allogeneic over autologous hematopoietic stem cell transplantation in patients with refractory or recurrent indolent non-Hodgkin's lymphoma Ann. Onc., May 1, 2003; 14(5): 737 - 744. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Ladetto, P. Corradini, S. Vallet, F. Benedetti, U. Vitolo, M. Martelli, M. Brugiatelli, P. Coser, A. Perrotti, I. Majolino, et al. High rate of clinical and molecular remissions in follicular lymphoma patients receiving high-dose sequential chemotherapy and autografting at diagnosis: a multicenter, prospective study by the Gruppo Italiano Trapianto Midollo Osseo (GITMO) Blood, August 13, 2002; 100(5): 1559 - 1565. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Hunault-Berger, N. Ifrah, and P. Solal-Celigny Intensive therapies in follicular non-Hodgkin lymphomas Blood, July 30, 2002; 100(4): 1141 - 1152. [Full Text] [PDF]
|
|
|
|
|
|
P. McLaughlin Profiling: "Editorial on 'Survival after progression in patients with follicular lymphoma: analysis of prognostic factors' ", by S. Montoto et al. (Ann Oncol 2002; 13: 523-530) Ann. Onc., April 1, 2002; 13(4): 499 - 500. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
