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Autologous Transplantation for Diffuse Aggressive Non-Hodgkin’s Lymphoma in Patients Never Achieving Remission: A Report from the Autologous Blood and Marrow Transplant Registry

From the Lymphoma Working Committee of the Autologous Blood and Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, WI; University of Nebraska Medical Center, Omaha, NE; Ireland Cancer Center, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, The Cleveland Clinic Foundation, Cleveland, and Miami Valley Hospital, Dayton, OH; University of Texas Health Science Center at San Antonio, San Antonio, TX; Fundaleu Hospital, Buenos Aires, Argentina; Princess Margaret Hospital, Toronto, Ontario, Canada; and University of Illinois, Chicago, IL.

Address reprint requests to Julie M. Vose, MD, Department of Internal Medicine, University of Nebraska Medical Center, 987680 Nebraska Medical Center, Omaha, NE 68198-7680; email jmvose{at}unmc.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To evaluate the results of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (autotransplants) in patients with diffuse aggressive non-Hodgkin’s lymphoma (NHL) who never achieve a complete remission with conventional chemotherapy.

PATIENTS AND METHODS: Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 184 patients with diffuse aggressive NHL who never achieved a complete remission with conventional chemotherapy and subsequently received an autotransplant were evaluated. Transplants were performed between 1989 and 1995 and were reported to the ABMTR by 48 centers in North and South America.

RESULTS: Seventy-nine (44%) of 184 patients achieved a complete remission or a complete remission with residual imaging abnormalities of unknown significance after autotransplantation. Thirty-four (19%) of 184 had a partial remission and 55 (31%) of 184 had no response or progressive disease. Eleven patients (6%) were not assessable for response because of early death. The probabilities of progression-free and overall survival at 5 years after transplantation were 31% (95% confidence interval [CI], 24% to 38%) and 37% (95% CI, 30% to 45%), respectively. In multivariate analysis, chemotherapy resistance, Karnofsky performance status score less than 80 at transplantation, age 55 years at transplantation, receiving three or more prior chemotherapy regimens, and not receiving pre- or posttransplant involved-field irradiation therapy were adverse prognostic factors for overall survival.

CONCLUSION: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation should be considered for patients with diffuse aggressive NHL who never achieve a complete remission but who are still chemotherapy-sensitive and are otherwise transplant candidates.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
ANTHRACYCLINE-BASED induction chemotherapy produces complete remission (CR) rates of 50% to 70% and long-term disease-free survival in approximately 40% of patients with diffuse aggressive non-Hodgkin’s lymphoma (NHL).^1-3 However, 30% to 50% of patients fail to achieve CR with standard induction therapy and require salvage therapy. Increasingly, salvage therapy strategies include high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (HSCT). Few large studies have been published of high-dose chemotherapy and autologous HSCT for patients with diffuse aggressive NHL who never achieve CR with conventional chemotherapy. We analyzed results of 184 patients with diffuse aggressive NHL who never achieved CR before undergoing high-dose chemotherapy and autologous HSCT as reported to the Autologous Blood and Marrow Transplant Registry (ABMTR). The purpose of this analysis was to determine progression-free and overall survival of this population and to identify patient-, disease-, and treatment-related variables correlated with outcome.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
ABMTR
The ABMTR is a voluntary organization of more than 170 transplant centers in the United States, Canada, and Central and South America that register consecutive autologous transplants with the ABMTR Statistical Center at the Medical College of Wisconsin. Data were collected prospectively by the ABMTR, starting in 1992. Retrospective data were collected for patients who received autologous transplants between 1989 and 1992. Participating centers register basic information on consecutive autologous transplants for all disease indications. Comprehensive clinical data are collected for a sample of these patients. Based on data collected in the Centers for Disease Control Hospital Surveys,⁴ approximately one half of autologous transplants in North America were registered with the ABMTR during that period. Physician review of submitted data, computerized error checks, and on-site audits were performed to ensure data accuracy. Patients are followed longitudinally, and information on disease-progression and death from any cause is updated yearly.

Patients
Between January 1, 1989, and December 30, 1995, 7,106 autologous transplants for all histologic subtypes of NHL were registered with the ABMTR; 2,252 cases had comprehensive reports submitted. Demographics and outcome of patients with and without comprehensive reports were similar. One hundred eighty-four patients with diffuse aggressive NHL (diffuse mixed small- and large-cell, diffuse large-cell, or diffuse large-cell immunoblastic according to the Working Formulation⁵) who had never achieved CR before transplant and had complete data reported to the ABMTR were evaluated in this analysis. Patients had to have completed at least one full regimen of combination chemotherapy (minimum of six cycles or 12 weeks) with an anthracycline-based regimen and have persistent NHL based on physical examinations and/or radiologic methods as appropriate for the individual patient. Some patients were rebiopsied at the physician’s discretion, but rebiopsy was not performed in all cases. The physicians were asked to distinguish between patients with active disease at the time of transplantation and those without active disease; the latter were excluded from this analysis. Therefore, patients with residual imaging abnormalities of uncertain significance (CRu) as a response to their initial therapy were not included in this analysis.

Statistical Methods
Probabilities of 100-day mortality (death from any cause in the first 100 days after transplantation), progression-free survival, and overall survival were calculated using the Kaplan-Meier product-limit estimate.⁶ CR was defined as complete disappearance of all abnormalities on physical examination, all imaging abnormalities, and all histologic evidence of lymphoma after transplantation. CR(u) was defined as minimal imaging abnormalities not thought to represent active disease. Partial remission (PR) was defined as a 50% or more reduction in all abnormalities on physical examination and/or imaging abnormalities after transplantation that lasted for 4 or more weeks. No response to transplant was defined as less than 50% reduction in all abnormalities on physical examination and/or imaging abnormalities after transplantation. Progression was defined as any increase in size of sites of disease, development of new sites of disease, or, in patients achieving CR, recurrence of disease. For calculations of survival and progression-free survival, patients were evaluated at the time of last follow-up. Chemotherapy sensitivity was defined as a reduction in measurable disease with salvage chemotherapy before transplantation that would meet PR criteria as defined above. Chemotherapy-resistant disease was defined as a reduction in measurable disease with salvage chemotherapy but less than that qualifying for PR. Patients designated as having unknown chemotherapy sensitivity status did not have adequate data available to make this designation.

Cox proportional hazards regression was used to examine the association between survival and patient-, disease-, and treatment-related variables.⁷ In the multivariate analysis, the following variables were evaluated for effects on overall survival: age at transplant (55 v < 55 years), sex, Karnofsky performance status score at transplant ( 80 v < 80), histology (diffuse large-cell, diffuse mixed, or immunoblastic), stage at diagnosis and before transplantation (I/II, III, or IV), presence of a large mediastinal mass at transplant ( 5 cm), bone marrow involvement, B symptoms at diagnosis, lactate dehydrogenase level at diagnosis (normal v higher than normal), chemotherapy sensitivity, number of prior chemotherapy regimens (one or two v three), interval from diagnosis to transplantation (6 months v 6 to 12 months v 12 to 24 months), high-dose therapy regimen (total-body irradiation [TBI] v non-TBI based), graft type (blood v marrow), graft manipulation (purging v none), hematopoietic growth factor given after transplantation (granulocyte v granulocyte-macrophage colony-stimulating factor v other), and year of transplantation (after 1993 v before 1993). The assumption of proportional hazards over time was tested for all explanatory covariates, by using a time-dependent covariate. The tests indicated that all covariates had constant relative risks over time. Forward step-wise model building was used. Within each model, one additional significant covariate factor was added at each step and the remaining factors were re-examined. When there were no further factors significant at the .05 significance level, model building was stopped. First-order interactions of significant covariates were tested.

Posttransplant Radiation Therapy
Studying effects of posttransplant maneuvers on outcome, such as posttransplant radiation therapy, must take into account any bias introduced by deaths that occurred before the intended treatments were administered, ie, patients who died before planned posttransplant radiation treatments could be administered would be considered in the no treatment group, although such treatment was planned. This bias artificially increases the proportion of adverse events in the nontreatment group if all patients are considered from the time of transplantation. This bias was overcome by studying only effects of posttransplant radiation therapy in patients already surviving more than 100 days after transplantation. Radiation therapy was analyzed in two groups: patients who received involved-field irradiation therapy given before or after transplantation versus no radiation therapy given before or after transplantation. One hundred fifty-one of 184 patients survived more than 100 days after transplantation.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient characteristics are listed in Table 1. At the time of transplantation, patients’ ages ranged from 9 to 69 years, with a median age of 42 years. Most lymphomas were categorized as diffuse large-cell (60%); diffuse mixed small- and large-cell lymphoma represented 15% of cases, and immunoblastic lymphoma represented 25% of cases. At the time of initial diagnosis, 63% of patients had stage III or IV disease, 54% had B symptoms, and 62 (67%) of 93 assessable patients had elevated lactate dehydrogenase levels. All patients received an anthracycline-containing chemotherapy regimen initially. One hundred seventy-six (96%) of 184 patients received one or more conventional salvage chemotherapy regimens before proceeding to high-dose chemotherapy and autologous HSCT. One hundred ten patients (60%) were thought to be chemotherapy-sensitive before transplantation, 52 (28%) were chemotherapy-resistant, and in 22 (12%), sensitivity was not assessable.

The median time from diagnosis to transplantation was 9 months; 27% of patients received transplants less than 6 months after diagnosis, 50%, 6 to 12 months after diagnosis, and 23%, 12 to 24 months after diagnosis. The most commonly used transplant preparative regimens were TBI plus chemotherapy (27%), carmustine, etoposide, cytarabine, and cyclophosphamide (27%), and cyclophosphamide, carmustine, and etoposide (19%). Fifty-six percent of patients received a bone marrow graft; 37% received a peripheral-blood stem-cell graft, and 7% received both products. Twenty-two patients (12%) received a stem-cell product that was manipulated by positive CD34⁺ cell selection or negative selection (purging) to remove lymphoma cells. Transplant-related characteristics are listed in Table 2.

With a median follow-up of 41 months (range, 24 to 103 months), the 5-year probabilities of progression-free survival and overall survival were 31% (95% CI, 24% to 38%) ( Fig 1) and 37% (95% CI, 30% to 45%) (Fig 1), respectively. The 100-day mortality rate was 18%; most deaths were due to recurrent or persistent NHL (20 of 33 patients [61%]). Other causes of 100-day mortality are listed in Table 3.

View larger version (20K): [in this window] [in a new window]   Fig 1. Probability of overall and progression-free survival in 184 patients who never achieved a CR before transplantation.

View larger version (19K): [in this window] [in a new window]   Fig 2. Probability of overall survival by chemotherapy sensitivity.

View larger version (18K): [in this window] [in a new window]   Fig 3. Probability of overall survival by Karnofsky performance status at the time of transplantation.

View larger version (17K): [in this window] [in a new window]   Fig 4. Probability of overall survival by age.

View larger version (17K): [in this window] [in a new window]   Fig 5. Probability of overall survival by the number of prior chemotherapy regimens.

View larger version (12K): [in this window] [in a new window]   Fig 6. Probability of overall survival by involved-field irradiation received by patients surviving 100 days after autotransplantation.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

However, the benefit of high-dose chemotherapy and autologous HSCT in patients who do not achieve CR with their initial induction chemotherapy remains controversial. An early study by Philip et al¹⁵ of 100 patients with relapsed or refractory NHL who received autotransplants identified few long-term disease-free survivors among those never in CR and with progressive disease before transplantation. Many subsequent studies of transplantation excluded such truly primary refractory patients from transplantation.

Several more-recent studies examined the role of high-dose chemotherapy and autologous HSCT in patients who did not achieve an initial CR but were still chemotherapy-sensitive at the time of transplantation. Mills et al¹⁶ evaluated 107 patients with relapsed and refractory NHL treated with autologous HSCT of whom 26 were identified as "first partial responders" at the time of transplantation. These 26 patients had a 5-year progression-free survival rate of 69%, compared with 32% for patients with chemotherapy-sensitive relapsed disease. In multivariate analysis of prognostic characteristics, only chemotherapy sensitivity status at transplantation was a significant predictor of outcome.¹⁶

In a report by Stiff et al,¹⁷ patients who received transplants for induction failure had a relapse rate of 59%, which did differ significantly from that of patients who received transplants while in resistant relapse. In another study from Stanford by Horning et al,¹⁸ 13 NHL patients who did not achieve CR with induction therapy were evaluated as part of a larger study of a cyclophosphamide, etoposide, and TBI regimen. With a median follow-up of 2.5 years and a maximum follow-up of 5 years, the freedom from progression was approximately 40%. Very similar results in 36 patients who received transplants for induction failure were reported by Prince et al.¹⁹ In the latter study, with a median follow-up of 28 months, event-free survival was 39%.

The only prospective randomized trial to address this question was published by Martelli et al.²⁰ In this trial, 77 (27%) of 286 patients with newly diagnosed NHL were considered to be in PR after completing two thirds of a front-line anthracycline regimen. Forty-nine of the 77 were randomized either to conventional salvage therapy (n = 27) or to high-dose therapy and autologous HSCT (n = 22). The overall response rate (CR + PR) after second-line therapy was 59% in the salvage chemotherapy group compared with 96% in the transplant group (P < .001). Progression-free survival was 52% in the salvage chemotherapy group and 73% in the transplantation group (P, not significant). Although there seemed to be a trend toward a better outcome with transplantation in this setting, the small number of patients randomized did not allow for an adequate test of the effects of transplantation.

The issue of identifying which patients with residual masses have active disease compared with those with fibrotic tissue is a difficult one. In a study by Verdonck et al,²¹ 69 patients with diffuse aggressive NHL with residual masses who were slow responders to induction chemotherapy were randomized for a comparison of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) versus high-dose chemotherapy and autologous stem-cell transplantation. In this analysis, there was no statistical difference between the two arms in overall or disease-free survival. The clinical situation in the Verdonck study is slightly different than in the current study because the patients in the randomized study went on to transplantation much earlier, after only three to four cycles of CHOP, and gallium scans were not used for most patients. The patients in the current study had received at least six cycles of an anthracycline therapy and many had received additional salvage chemotherapy before transplantation. In addition, in the present trial, patients were included who had bone marrow positivity, many extranodal sites of disease, or gallium positivity. These characteristics would make the likelihood of residual masses being fibrotic tissue alone less likely.

The last international consensus conference on high-dose chemotherapy and stem-cell transplantation for lymphoma reviewed the issue of transplantation in patients with incomplete responses to standard induction chemotherapy. In this review, the studies were analyzed and thought to have insufficient numbers of patients included in the trials to draw a definite conclusion on the role of transplantation in this circumstance.²²

The current study represents the largest available data set of patients with diffuse aggressive NHL undergoing transplantation after not achieving CR with induction chemotherapy. Our data demonstrate 5-year probabilities of progression-free and overall survival of 31% and 37%, respectively. This confirms several recently published studies containing small numbers of patients that also demonstrate event-free survivals between 30% and 40% in this patient population.^18,19 Because this current data set contains 184 patients, a multivariate analysis of prognostic factors was possible. Also, as reported in previous smaller studies, chemotherapy sensitivity status at transplantation is an important predictor. Additional characteristics associated with a poor outcome included a Karnofsky performance status score of less than 80 at transplantation, age 55 years at transplantation, three or more prior chemotherapy regimens before transplantation, and no pre- or posttransplant involved-field irradiation.

These results highlight several issues for discussion. In any nonrandomized transplantation study, the issue of patient selection must be addressed. Many patients for whom transplantation is considered may not receive a transplant because of comorbid medical illness, insurance difficulties, progressive lymphoma, and other issues. Consequently, this and other single-arm studies have an inherent selection bias. One must consider this when applying the findings to a general lymphoma population in this clinical situation. Additionally, as with Hodgkin’s disease, some patients have residual CT scan abnormalities after induction therapy that may represent only fibrotic or necrotic tissue and not active disease.²³ Therefore, salvage therapy, whether conventional chemotherapy or transplantation, could be applied to a patient who may already be cured with their induction regimen. It is possible that other tests that test metabolic activity of tissues, such as the single-photon emission computed tomography gallium scan or fluorodeoxyglucose–positron emission tomography, may be beneficial in identifying patients with active disease compared with fibrotic tissue.^24,25 However, further evaluation of these techniques is necessary and most are not routinely used.

Most of the characteristics identified in the prognostic factor analysis are well known to demonstrate poor prognosis in most NHL transplantation studies, such as chemotherapy resistance, older age, poor performance status, and having received multiple prior chemotherapies before transplantation. The issue of involved-field irradiation is an interesting topic. Typically involved-field irradiation is given to patients with more localized disease and, therefore, may be a surrogate that represents limited disease in this analysis. However, the stage of the patients at transplantation and the presence of a large mediastinal mass were not significant in the multivariate analysis. Therefore no direct correlation can be identified. A more thorough analysis of involved-field irradiation given in conjunction with transplantation is warranted.

Our data demonstrate that some patients with aggressive NHL who do not achieve a CR with an induction regimen can have long-term disease-free survival with high-dose therapy and autologous HSCT. Patients who seem to benefit most from this approach are those who remain chemotherapy-sensitive, have a good performance status, are younger than 55 years of age, have received only one or two prior chemotherapy regimens, and have received either pre- or posttransplant involved-field irradiation. Evaluation in clinical trials of newer transplantation techniques, such as the addition of antibodies or immunologic agents to the transplant regimen or, alternatively, allogeneic transplants with or without donor leukocyte infusion, should be explored in patients in the poor prognosis groups.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Other Authors on the Autologous Blood and Marrow Transplant Registry Lymphoma Working Committee
The other authors on the Autologous Blood and Marrow Transplant Registry Lymphoma Working Committee are as follows: Asad Bashey, MD, Blood and Marrow Transplantation, University of California, San Diego, CA; Isabelle Bence-Bruckler, MD, FRCPC, Department of Hematology, University of Ottawa, Ottawa, Ontario, Canada; Linda J. Burns, MD, Department of Medicine, University of Minnesota, Minneapolis, MN; Joseph W. Fay, MD, Department of Hematology/Oncology, Baylor University Medical Center, Dallas, TX; Robert Peter Gale, MD, PhD, Division of Bone Marrow and Stem Cell Transplantation, Salick Healthcare, Inc, Los Angeles, CA; John Gibson, MD, Department of Haematology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia; Sergio A. Giralt, MD, M.D. Anderson Cancer Center, University of Texas, Houston, TX; Steven Goldstein, MD, H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, FL; Roger H. Herzig, MD, Department of Medicine, James Graham Brown Cancer Center, University of Louisville, Louisville, KY; Wolfgang Hiddemann, MD, Ludwig-Maximilians University, Munich, Germany; Rodrigo Martino, MD, Hospital Sant Pau, Barcelona, Spain; Philip L. McCarthy, MD, Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY; Alan Miller, MD, Bone Marrow Transplant Program, Tulane University Medical Center, New Orleans, LA; Gustavo Milone, MD, Fundaleu Hospital, Buenos Aires, Argentina; Emilio Montserrat, MD, University of Barcelona, Spain; Andrew Pecora, MD, Hackensack University Medical Center, Hackensack, NJ; Gordon L. Phillips, MD, Markey Cancer Center, University of Kentucky, Lexington, KY; Arnold D. Rubin, MD, Hematology/Oncology, St Joseph’s Hospital Medical Center, Paterson, NJ; David P. Schenkein, MD, Tufts University School of Medicine, Boston, MA; Patrick J. Stiff, MD, Loyola University Medical Center, Maywood, IL; David H. Vesole, MD, PhD, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI; and John R. Wingard, MD, University of Florida, Gainesville, FL.

	ACKNOWLEDGMENTS

 
Supported by Public Health Service grants no. P01-CA-40053 and no. U24-76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute of the United States Department of Health and Human Services; and by grants from Alpha Therapeutic Corporation; Amgen Inc; Anonymous; Baxter Fenwal; Berlex Laboratories; BioWhittaker, Inc; Blue Cross and Blue Shield Association; Bristol-Myers Squibb Company; Cell Therapeutics, Inc; Centeon; Center for Advanced Studies in Leukemia; Chimeric Therapies, Inc; Chiron Therapeutics; COBE BCT, Inc; The Eppley Foundation for Research; Fujisawa Healthcare, Inc; Genentech, Inc; Human Genome Sciences; Immunex Corporation; The Kettering Family Foundation; Kirin Brewery Company; Robert J. Kleberg, Jr, and Helen C. Kleberg Foundation; Mayer Ventures; Milstein Family Foundation; Milwaukee Foundation/Elsa Schoeneich Research Fund; Nexell Therapeutics, Inc; NeXstar Pharmaceuticals, Inc; Novartis Pharmaceuticals; Orphan Medical; Ortho Biotech, Inc; Pharmacia and Upjohn; Pfizer, Inc; Roche Laboratories; SangStat Medical Corporation; Schering AG; Schering Oncology; Searle; SmithKline Beecham Pharmaceutical; SyStemix; TheraTechnologies, and United Resource Networks.

	NOTES

 
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

For the names of the other authors on the ABMTR Lymphoma Working Committee, see the Appendix.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
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10. Gribben JG, Goldstone AH, Linch DC, et al: Effectiveness of high dose combination chemotherapy and ABMT for patients with NHL who are still responsive to conventional dose chemotherapy. J Clin Oncol 7: 1621-1629, 1989[Abstract]

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16. Mills W, Chopra R, McMillan A, et al: BEAM chemotherapy and autologous bone marrow transplantation for patients with relapsed or refractory non-Hodgkin’s lymphoma. J Clin Oncol 13: 588-595, 1995[Abstract/Free Full Text]

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Submitted October 20, 1999; accepted August 25, 2000.

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