Originally published as JCO Early Release 10.1200/JCO.2006.09.1215 on February 20 2007

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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gopal, A. K. Articles by Press, O. W. Search for Related Content PubMed PubMed Citation Articles by Gopal, A. K. Articles by Press, O. W.

High-Dose [¹³¹I]Tositumomab (anti-CD20) Radioimmunotherapy and Autologous Hematopoietic Stem-Cell Transplantation for Adults 60 Years Old With Relapsed or Refractory B-Cell Lymphoma

Ajay K. Gopal, Joseph G. Rajendran, Ted A. Gooley, John M. Pagel, Darrell R. Fisher, Stephen H. Petersdorf, David G. Maloney, Janet F. Eary, Frederick R. Appelbaum, Oliver W. Press

From the Department of Medicine, Division of Medical Oncology; the Department of Radiology, Division of Nuclear Medicine, University of Washington; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; and the Pacific Northwest National Laboratory, Richland, WA

Address reprint requests to Ajay K. Gopal, MD, University of Washington/Seattle Cancer Care Alliance, 825 Eastlake Ave E G6-800, Seattle, WA 98195; e-mail: agopal{at}u.washington.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Purpose: The majority of patients with relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL) are older than 60 years, yet they are often denied potentially curative high-dose therapy and autologous stem-cell transplantations (ASCT) because of the risk of excessive treatment-related morbidity and mortality. Myeloablative anti-CD20 radioimmunotherapy (RIT) can deliver curative radiation doses to tumor sites while limiting exposure to normal organs and may be particularly suited for older adults requiring high-dose therapy.

Patients and Methods: Patients older than 60 years with relapsed B-cell NHL (B-NHL) received infusions of tositumomab anti-CD20 antibody labeled with 185 to 370 Mbq (5 to 10 mCi) [¹³¹I]-tracer for dosimetry purposes followed 10 days later by individualized therapeutic infusions of [¹³¹I]tositumomab (median, 19.4 Gbq [525 mCi]; range, 12.1 to 42.7 Gbq [328 to 1,154 mCi]) to deliver 25 to 27 Gy to the critical normal organ receiving the highest radiation dose. ASCT was performed approximately 2 weeks after therapy.

Results: Twenty-four patients with a median age of 64 years (range, 60 to 76 years), who had received a median of four prior regimens (range, two to 14 regimens), were treated. Thirteen patients (54%) had chemotherapy-resistant disease. The estimated 3-year overall and progression-free survival rates were 59% and 51%, respectively, with a median follow-up of 2.9 years (range, 1 to 6 years). All patients experienced expected myeloablation with engraftment of platelets ( 20 K/µL) and neutrophils ( 500/µL), occurring at a median of 9 and 15 days after ASCT, respectively. There were no treatment-related deaths, and only two patients experienced grade 4 nonhematologic toxicity.

Conclusion: Myeloablative RIT and ASCT is a safe and effective therapeutic option for older adults with relapsed B-NHL.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Non-Hodgkin's lymphoma (NHL) is diagnosed in nearly 60,000 individuals each year in the United States, with more than half of these diagnoses occurring in adults older than 60 years.¹ Recent advances in the initial therapy of NHL have improved response rates and remission durations in older adults with B-cell NHL (B-NHL), but most older patients eventually relapse.^2-4 Several studies have shown that advanced age is independently associated with inferior outcome in NHL.^5,6 For younger adults, randomized trials have suggested that high-dose therapy followed by autologous hematopoietic stem-cell transplantation (ASCT) improves overall survival (OS) and/or progression-free survival (PFS) in certain settings.^7-9 However, historically the vast majority of the prospective randomized trials excluded patients older than 60 years because of concerns over toxicity.^7,8,10-18 These concerns are supported by most retrospective series suggesting that ASCT in older adults, though feasible, carries greater morbidity and mortality risks. ^19-21

High-dose radioimmunotherapy (RIT) can deliver potentially curative radiation to tumor sites while limiting the relative radiation exposure to non–target organs.^22-24 Previous phase I/II studies by our group in younger patients have established that up to 27 Gy of radiation can be delivered to critical normal organs with limited nonhematologic toxicity and maintained efficacy.^25,26 We, thus, hypothesized that this targeted strategy may be ideal for older adults. We now report the results of a phase II trial evaluating the safety and efficacy of myeloablative RIT followed by ASCT in patients 60 years old with relapsed or refractory B-NHL.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Patients
Patients with relapsed or refractory CD20 expressing B-NHL were required to have reached their 60th birthday before initiation of therapy to be eligible. Other eligibility criteria included standard transplantation criteria, such as a normal cardiac ejection fraction, FEV1 (forced expiratory volume in 1 second) 70% of predicted, serum creatinine less than 2.0 mg/dL, serum bilirubin less than 1.5 mg/dL, absence of serious infection, a performance status of 0 to 1, and availability of 2 x 10⁶ autologous CD34 positive cells/kg of body weight. Patients with evidence of tumor contamination of the peripheral blood as determined by flow cytometry at the time of collection were required to undergo CD34 selection of the hematopoietic stem cells. Patients were excluded if they lacked assessable disease, had CNS lymphoma, had previously received more than 20 Gy irradiation to critical organs or to more than 25% of red marrow, had received antilymphoma therapy within 30 days, had a prior stem-cell transplantation, or had evidence of human antimouse antibodies. Small lymphocytic lymphoma patients were excluded due to low CD20 expression. Patients with tumor bulk more than 500 mL (roughly the size of a 9.8-cm diameter spherical mass) or splenomegaly more than 6.9 mL/kg ideal body weight (approximately a 16 x 8 cm ellipsoid for an 80-kg patient) were required to undergo cytoreduction or splenectomy in order to optimize biodistribution of the radioimmunoconjugate.²² The institutional review boards of the Fred Hutchinson Cancer Research Center and the University of Washington (both in Seattle, WA) approved this protocol and all patients provided written informed consent. The protocol was registered at http://www.clinicaltrials.gov (NCT00073931 [ClinicalTrials.gov] ).

Biodistribution Studies
The overall schema is illustrated in Figure 1. The anti-CD20 antibody tositumomab (provided by GlaxoSmithKline, Philadelphia, PA) was radioiodinated with 185 to 370 Mbq (5 to 10 mCi) of [¹³¹I] as previously described.^22,27 Patients were infused without premedication over 1 hour as outpatients using 1.7 mg/kg of trace-labeled [¹³¹I]tositumomab. Serial gamma camera images were obtained immediately after infusion, and at 48, 120, and 144 hours after infusion to determine tracer biokinetics for estimating radiation dose to critical organs and whole body as previously described.^25,28 Organ doses were obtained by integrating the time-activity curves and applying the calculation methods recommended by the Medical Internal Radiation Dose Committee of the Society of Nuclear Medicine (Reston, VA).²⁹ Thyroid uptake was blocked with oral potassium iodide, starting 24 hours before the dosimetric dose and continued for 30 days.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Treatment schema for high-dose radioimmunotherapy and autologous stem-cell transplantation (ASCT) in older adults. Note: The days of discharge from radiation isolation and ASCT are estimates. The actual dates are determined by the individual patient's radiation exposure.

Hematopoietic Stem-Cell Infusion and Supportive Care
Cyropreserved hematopoietic stem cells were thawed and infused when the patient's whole body gamma emission was predicted to be 0.02 mSv/h ( 2 mrem/h) at 1 meter. In general, fluconazole, trimethoprim-sulfamethoxazole, and acyclovir were given prophylactically, and levofloxacin was administered when the neutrophil count dropped below 500/µL. Transfusions of platelets and RBCs were administered at values less than 10,000/µL and 25%, respectively. Hematopoietic growth factors were not routinely utilized.

Follow-Up and Statistical Analysis
Patients were evaluated with computed tomography at baseline, 1, 3, 6, and 12 months, and then annually after transplantation. Blood and bone marrow were evaluated by morphology, flow cytometry, and polymerase chain reaction designed to detect clonal CDRIII rearrangements of the immunoglobulin heavy chain locus and translocations of t(14;18) or t(11;14) assays pretherapy, at 1 month after transplantation, and annually thereafter. Bone marrow cytogenetics were evaluated pretherapy, at 1 month after therapy, and then annually. All toxicities were captured and scored based on the National Cancer Institute Common Toxicity Criteria scale (NCI-CTC) version 2.0 and on the Bearman transplant scale.³⁰ The lymphoma international prognostic index (IPI) and the follicular lymphoma international prognostic index (FLIPI) were calculated based on the nodal areas and extranodal sites, as well as stage, performance status, age, serum lactate dehydrogenase, and hemoglobin at the time of therapy.^5,6 Responses were assessed according to the criteria of an international working group.³¹ Patients achieving less than a partial response (PR) from the regimen immediately preceding this therapy were categorized as having "chemoresistant" disease. Progression was defined as any clinical, radiographic, morphologic, or flow cytometric documentation of increasing disease burden or treatment for suspected progression.

The primary end point of this study was PFS. Secondary end points included OS, toxicity, treatment-related mortality, and nonrelapse mortality. Treatment-related mortality was defined as death without prior disease progression. Probabilities of OS and PFS were estimated using the method of Kaplan and Meier.³² The study was designed to have approximately 80% power (77% power using Fisher's exact test, 85% power using the ² test) to deem the observed estimate of PFS at 5 years as statistically significantly (at the one-sided level of significance of .05) higher than the fixed rate of 10% under the assumption that the true 5-year PFS is 30%.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Patients
Twenty-five patients were enrolled and 24 patients completed therapy between December 1, 1999, and April 29, 2005. One patient was noted to have human antimouse antibodies before dosimetry and was taken off study. Baseline characteristics are noted in Table 1. The median age at transplantation of the treated patients was 64 years, with a range from 60 to 76 years. Ninety-six percent of patients had stage III/IV disease, 46% had an elevated lactate dehydrogenase before therapy, 17% had more than one extranodal lymphomatous site, and all patients had performance status of 0 to 1. Patients had failed a median of four regimens (range, two to 14 regimens). Eighteen patients (75%) had failed prior rituximab and 13 patients (54%) were scored as chemotherapy-resistant. Nine patients had diffuse large B-cell lymphoma (DLBCL); four of the nine patients had disease transformed from follicular lymphoma (FL). Eight patients had mantle-cell lymphoma (MCL), six patients had grades 2 or 3 FL, and one patient had marginal zone lymphoma (MZL). The FLIPI scores for the six FL patients were: 2 (n = 3), 3 (n = 1), and 4 (n = 2), whereas the IPI scores for the remaining 18 patients included: 2 (n = 10), 3 (n = 4), and 4 (n = 4). Seven patients (29%) had been referred by other transplantation centers because of either high-risk features or advanced age.

Response, Overall, and Progression-Free Survival
The overall response rate was 67%, with 13 patients attaining a complete response or complete-response unconfirmed and three patients attaining a PR with a median time from transplantation to best response in responding patients of 96 days (range, 25 days to 2.1 years). Six patients had stable disease and two patients experienced progressive lymphoma at the initial disease restaging. The estimated 3-year OS and PFS were 59% (95% CI, 37% to 80%) and 51% (95%, CI 30% to 72%), respectively (Fig 2), with a median follow-up from transplantation of 2.9 years (range, 1.0 to 6.0 years) among 15 patients surviving as of last contact (July 1, 2006). The estimated 3-year OS and PFS for the MCL, FL/MZL, and DLBCL groups are illustrated in Figure 3. The outcome among 10 patients with chemotherapy-sensitive disease was similar to that among 13 patients with chemotherapy-resistant disease (six [60%] of 10 patients v eight [62%] of 13 patients surviving, hazard ratio [HR] = 0.96; four [40%] of 10 patients v five [38%] of 13 patients alive and progression-free, HR = 0.88). Of the six patients who had baseline molecular evidence of lymphoma before therapy, four attained molecular remissions 1 to 12 months after therapy.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Overall and progression-free survival. Twenty-four adults age 60 years following high-dose [131I]tositumomab and autologous stem-cell transplantation.

View larger version (16K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. (A) Overall survival and (B) progression-free survival (PFS) grouped by histology. MCL, mantle-cell lymphoma; FL, follicular lymphoma; MZL, marginal zone lymphoma; DLBCL, diffuse large B-cell lymphoma.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
In this study, we demonstrate that single agent [¹³¹I]tositumomab given at a myeloablative dose is a safe and effective conditioning regimen for older patients with relapsed or refractory B-NHL who are undergoing ASCT. These results add a novel prospectively assessed treatment strategy to the emerging literature on high-dose therapy and ASCT in older adults. Most early reports of ASCT for relapsed NHL in adults older than 50 to 60 years show a clear association between increasing age and more frequent toxicities and 100-day treatment-related mortality rates of 9% to 28%.^19-21,33-35 A more recent review by Jantunen³⁶ of all reported series of 10 patients older than 60 years who underwent ASCT for NHL concluded that this therapy was feasible in selected older adults, but carried higher morbidity than was observed in younger patients, with the larger series (> 20 patients) reporting early treatment-related mortality rates of 5.4% to 11%. The two largest retrospective studies reported excessive rates of early death from both infections and direct organ toxicity, even when less toxic regimens such as carmustine, etoposide, cytarabine, and melaphalan (BEAM) were administered.^19,37 This observed correlation between advancing age and increasing toxicity may be explained in part by the association of advanced age with reductions in tissue repair capacity and greater variability in drug metabolism, emphasizing the importance of approaches that limit normal organ exposure to cytotoxic agents.^38-41

In contrast to conventional conditioning regimens, the relatively specific targeting of RIT to tumor sites in our study may have limited both direct toxicity to normal organs as well as attenuated infectious complications by obviating the destruction of mucosal barriers. Furthermore, unlike traditional high-dose chemotherapy, the individualized dosimetry used to calculate the specific therapeutic [¹³¹I] dose for each patient may have also overcome patient-to-patient differences in pharmacokinetics. Importantly, this targeted approach yielded no treatment-related deaths, and grade 4 nonhematologic toxicity was limited to two patients. Even more notable may be the observation that only eight (33%) of 24 patients required intravenous fluids or total parenteral nutrition for mucositis, nausea, and anorexia, which are typically expected in most ASCT patients receiving conventional conditioning regimens. Similar toxicities were observed in prior studies utilizing this regimen in younger (median age, 47 years), less heavily pretreated patients (median of two prior regimens), demonstrating that rates of early nonrelapse mortality trended lower than non–randomly assigned controls (3.7% v 11.7%; P = .06), and severe nonhematologic toxicities were only predictably observed when they occurred above the maximally tolerated dose of 27 Gy.²³

Another observation from this study was that the neutrophil engraftment appeared after platelet recovery. This phenomenon parallels the findings of earlier publications using this regimen in younger patients in whom bone marrow was the major source of autologous stem cells and platelet engraftment preceded neutophils by a median of 1 to 2 days.^22,25 One could hypothesize that the tositumomab itself may have contributed to the difference as prior data have suggested an association of unlabeled anti-CD20 antibody therapy (rituximab) with neutropenia, which may have been further exacerbated in our study by the use of peripheral blood as the stem cell source and the lack of granulocyte colony-stimulating factor use after stem-cell infusion.^42-44 Despite the gradual neutrophil engraftment there were no grade 4 to 5 infections.

Another concern of high-dose therapy and ASCT is the risk of secondary malignancies, particularly myelodysplastic syndrome/acute myeloid leukemia (MDS/AML). A variety of predictive factors have been suggested for MDS/AML, including radiation-based conditioning, etoposide, fludarabine, alkylating agents, and extensive prior therapy in general.^45-49 Two patients (8.3%) in our study developed clinical MDS/AML, a rate that is comparable with other series.^46,49 Other reports have suggested that patients who received four prior regimens have a five-fold increased risk of developing MDS and that older age is also independently associated with developing MDS.^45,47 These factors may have also contributed to the two instances of MDS in our series, since all patients were older than 60 years and had received a median of four prior regimens. Interestingly, the remaining two patients with new cytogenetic abnormalities without MDS exhibited a deletion of the Y chromosome in a minority of cells, a finding that has been observed in normal older males.⁵⁰

The estimated progression-free survival rate of 51% at 3 years after transplantation is similar to other transplantation series in younger adults, which have generally been limited to chemotherapy-sensitive relapsed B-NHL.^7,51-54 Prior studies of anti-CD20 RIT have suggested that on average the radiation dose to tumor is twice the absorbed dose to the critical normal organ receiving the most radiation, potentially explaining the apparent efficacy of this strategy.²² It is possible that the adverse impact of chemotherapy-resistance may have been abrogated by the use of a less cross-resistant radiation-based approach, though the sample size and nonrandomized nature of these results make definite conclusions difficult. Comparisons with prior studies using high-dose [¹³¹I]tositumomab and ASCT in younger adults are challenging, as most prior patients had follicular lymphoma and were less heavily pretreated.^23,26 Ultimately, this strategy will need to be compared in a randomized fashion to more conventional regimens, such as BEAM, that are commonly administered to older populations.³⁶ Further studies by our group are also focusing on improving the PFS by adding concurrent fludarabine, which has been shown to synergize with RIT in vitro.⁵⁵

Like cancer in general, NHL will continue to have an impact on a larger number of older patients as the population ages and life expectancies rise for adults older than 60 years.^56-58 Despite this increasing preponderance of older adults with cancer, registry data suggest that only one third of patients on National Institutes of Health–sponsored oncology trials are older than 60 years and only 14% of lymphoma patients on Southwest Oncology Group studies were older than 65 years.^59,60 Targeted and pharmacokinetically dosed agents may abrogate some of the toxicity concerns about aggressively treating older populations and allow extension of effective therapies to patients of all ages. This study provides the first suggestion that myeloablative [¹³¹I]tositumomab is a promising modality with limited toxicity for adults with B-NHL who are older than 60 years, though larger multicenter trials are needed to confirm these findings.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

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

Employment: N/A Leadership: N/A Consultant: Oliver W. Press, GlaxoSmithKline, Genentech Stock: N/A Honoraria: N/A Research Funds: Ajay K. Gopal, GlaxoSmithKline Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
Conception and design: Ajay K. Gopal, Joseph G. Rajendran, Ted A. Gooley, John M. Pagel, David G. Maloney, Frederick R. Appelbaum, Oliver W. Press

Provision of study materials or patients: Ajay K. Gopal, Joseph G. Rajendran, John M. Pagel, Stephen H. Petersdorf, David G. Maloney, Janet F. Eary, Oliver W. Press

Collection and assembly of data: Ajay K. Gopal, Joseph G. Rajendran

Data analysis and interpretation: Ajay K. Gopal, Joseph G. Rajendran, Ted A. Gooley, Darrell R. Fisher

Manuscript writing: Ajay K. Gopal, Joseph G. Rajendran, Ted A. Gooley, Oliver W. Press

Final approval of manuscript: Ajay K. Gopal, Joseph G. Rajendran, Ted A. Gooley, John M. Pagel, Darrell R. Fisher, Stephen H. Petersdorf, David G. Maloney, Janet F. Eary, Frederick R. Appelbaum, Oliver W. Press

	ACKNOWLEDGMENTS

 
Special thanks to Sharon Bush, RN, Donna Kelly, RN, Jill Loveland, RN, Martha Bien, Jennifer Davies, Lawrence Durack, Carolyn Thostenson, Lacey Drouet, Nathan Hedin, and Mark Brockman, as well as the patients, caregivers, and providers who helped make this study possible.

	NOTES

 
published online ahead of print at www.jco.org on February 20, 2007.

Supported by Grants No. P01CA44991, K23CA85479, KO8CA95448, from the National Cancer Institute, the Lymphoma Research Foundation Mantle Cell Lymphoma Research Initiative, and a gift from Frank and Betty Vandermeer. J.M.P. is a recipient of Lymphoma Research Foundation Career Development award and a Scholar of the Damon Runyon Cancer Research Foundation.

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

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS REFERENCES

 
1. Jemal A, Murray T, Ward E, et al: Cancer statistics, 2005. CA Cancer J Clin 55:10-30, 2005[Abstract/Free Full Text]

2. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002[Abstract/Free Full Text]

3. Romaguera JE, Fayad L, Rodriguez MA, et al: High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol 23:7013-7023, 2005[Abstract/Free Full Text]

4. Marcus R, Imrie K, Belch A, et al: CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 105:1417-1423, 2005[Abstract/Free Full Text]

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

6. Solal-Celigny P, Roy P, Colombat P, et al: Follicular lymphoma international prognostic index. Blood 104:1258-1265, 2004[Abstract/Free Full Text]

7. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333:1540-1545, 1995[Abstract/Free Full Text]

8. Schouten HC, Qian W, Kvaloy S, et al: 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 21:3918-3927, 2003[Abstract/Free Full Text]

9. Dreyling M, Lenz G, Hoster E, et al: Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: Results of a prospective randomized trial of the European MCL Network. Blood 105:2677-2684, 2005[Abstract/Free Full Text]

10. Santini G, Salvagno L, Leoni P, et al: VACOP-B versus VACOP-B plus autologous bone marrow transplantation for advanced diffuse non-Hodgkin's lymphoma: Results of a prospective randomized trial by the non-Hodgkin's Lymphoma Cooperative Study Group. J Clin Oncol 16:2796-2802, 1998[Abstract]

11. Kaiser U, Uebelacker I, Abel U, et al: Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma. J Clin Oncol 20:4413-4419, 2002[Abstract/Free Full Text]

12. Martelli M, Gherlinzoni F, De Renzo A, et al: Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: An Italian multicenter randomized trial. J Clin Oncol 21:1255-1262, 2003[Abstract/Free Full Text]

13. Milpied N, Deconinck E, Gaillard F, et al: Initial treatment of aggressive lymphoma with high-dose chemotherapy and autologous stem-cell support. N Engl J Med 350:1287-1295, 2004[Abstract/Free Full Text]

14. Lenz G, Dreyling M, Schiegnitz E, 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 104:2667-2674, 2004[Abstract/Free Full Text]

15. Deconinck E, Foussard C, Milpied N, 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 105:3817-3823, 2005[Abstract/Free Full Text]

16. Vitolo U, Liberati AM, Cabras MG, et al: High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: An "Intergruppo Italiano Linfomi" randomized trial. Haematologica 90:793-801, 2005[Abstract/Free Full Text]

17. Olivieri A, Santini G, Patti C, et al: Upfront high-dose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin's lymphoma: Long-term results by the NHLCSG. Ann Oncol 16:1941-1948, 2005[Abstract/Free Full Text]

18. Sebban C, Mounier N, Brousse N, 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 108:2540-2544, 2006[Abstract/Free Full Text]

19. Jantunen E, Itala M, Juvonen E, et al: Autologous stem cell transplantation in elderly (> 60 years) patients with non-Hodgkin's lymphoma: A nation-wide analysis. Bone Marrow Transplant 37:367-372, 2006[CrossRef][Medline]

20. Gopal AK, Gooley TA, Golden JB, et al: Efficacy of high-dose therapy and autologous hematopoietic stem cell transplantation for non-Hodgkin's lymphoma in adults 60 years of age and older. Bone Marrow Transplant 27:593-599, 2001[CrossRef][Medline]

21. Kusnierz-Glaz CR, Schlegel PG, Wong RM, et al: Influence of age on the outcome of 500 autologous bone marrow transplant procedures for hematologic malignancies. J Clin Oncol 15:18-25, 1997[Abstract/Free Full Text]

22. Press OW, Eary JF, Appelbaum FR, et al: Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support. N Engl J Med 329:1219-1224, 1993[Abstract/Free Full Text]

23. Gopal AK, Gooley TA, Maloney DG, 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 102:2351-2357, 2003[Abstract/Free Full Text]

24. Nademanee A, Forman S, Molina A, et al: A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood 106:2896-2902, 2005[Abstract/Free Full Text]

25. Press OW, Eary JF, Appelbaum FR, et al: Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation for relapsed B cell lymphomas. Lancet 346:336-340, 1995[CrossRef][Medline]

26. 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 16:3270-3278, 1998[Abstract]

27. Eary JF, Press OW, Badger CC, et al: Imaging and treatment of B-cell lymphoma. J Nucl Med 31:1257-1268, 1990[Abstract/Free Full Text]

28. Rajendran JG, Fisher DR, Gopal AK, et al: High-dose (131)I-tositumomab (anti-CD20) radioimmunotherapy for non-Hodgkin's lymphoma: Adjusting radiation absorbed dose to actual organ volumes. J Nucl Med 45:1059-1064, 2004[Abstract/Free Full Text]

29. Loevenger R, Budinger T, Watson E: Primer for Absorbed Dose Calculations. New York, NY, The Society of Nuclear Medicine, 1991

30. Bearman SI, Appelbaum FR, Buckner CD, et al: Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 6:1562-1568, 1988[Abstract/Free Full Text]

31. Cheson BD, Horning SJ, Coiffier B, et al: Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244-1253, 1999[Abstract/Free Full Text]

32. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef]

33. Sweetenham JW, Pearce R, Philip T, et al: High-dose therapy and autologous bone marrow transplantation for intermediate and high grade non-Hodgkin's lymphoma in patients aged 55 years and over: Results from the European Group for Bone Marrow Transplantation—The EBMT Lymphoma Working Party. Bone Marrow Transplant 14:981-987, 1994[Medline]

34. Miller CB, Piantadosi S, Vogelsang GB, et al: Impact of age on outcome of patients with cancer undergoing autologous bone marrow transplant. J Clin Oncol 14:1327-1332, 1996[Abstract/Free Full Text]

35. Bitran JD, Klein L, Link D, et al: High-dose myeloablative therapy and autologous peripheral blood progenitor cell transplantation for elderly patients (greater than 65 years of age) with relapsed large cell lymphoma. Biol Blood Marrow Transplant 9:383-388, 2003[CrossRef][Medline]

36. Jantunen E: Autologous stem cell transplantation beyond 60 years of age. Bone Marrow Transplant 38:715-720, 2006[CrossRef][Medline]

37. Buadi FK, Micallef IN, Ansell SM, et al: Autologous hematopoietic stem cell transplantation for older patients with relapsed non-Hodgkin's lymphoma. Bone Marrow Transplant 37:1017-1022, 2006[CrossRef][Medline]

38. Baker SD, Grochow LB: Pharmacology of cancer chemotherapy in the older person. Clin Geriatr Med 13:169-183, 1997[Medline]

39. Byrne A, Carney DN: Cancer in the elderly. Curr Probl Cancer 17:145-218, 1993[Medline]

40. Balducci L, Lyman GH: Cancer in the elderly: Epidemiologic and clinical implications. Clin Geriatr Med 13:1-14, 1997[Medline]

41. Repetto L: Greater risks of chemotherapy toxicity in elderly patients with cancer. J Support Oncol 1:18-24, 2003[Medline]

42. Cattaneo C, Spedini P, Casari S, et al: Delayed-onset peripheral blood cytopenia after rituximab: Frequency and risk factor assessment in a consecutive series of 77 treatments. Leuk Lymphoma 47:1013-1017, 2006[CrossRef][Medline]

43. Chaiwatanatorn K, Lee N, Grigg A, et al: Delayed-onset neutropenia associated with rituximab therapy. Br J Haematol 121:913-918, 2003[CrossRef][Medline]

44. Nitta E, Izutsu K, Sato T, et al: A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20-positive B-cell lymphoma: A single-institution study. Ann Oncol, 18:364-369, 2007 [epub ahead of print on November 1, 2006][Abstract/Free Full Text]

45. Kalaycio M, Rybicki L, Pohlman B, et al: Risk factors before autologous stem-cell transplantation for lymphoma predict for secondary myelodysplasia and acute myelogenous leukemia. J Clin Oncol 24:3604-3610, 2006[Abstract/Free Full Text]

46. Armitage JO, Carbone PP, Connors JM, et al: Treatment-related myelodysplasia and acute leukemia in non-Hodgkin's lymphoma patients. J Clin Oncol 21:897-906, 2003[Abstract/Free Full Text]

47. Micallef IN, Lillington DM, Apostolidis J, et al: Therapy-related myelodysplasia and secondary acute myelogenous leukemia after high-dose therapy with autologous hematopoietic progenitor-cell support for lymphoid malignancies. J Clin Oncol 18:947-955, 2000[Abstract/Free Full Text]

48. Metayer C, Curtis RE, Vose J, et al: Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: A multicenter case-control study. Blood 101:2015-2023, 2003[Abstract/Free Full Text]

49. Krishnan A, Bhatia S, Slovak ML, et al: Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: An assessment of risk factors. Blood 95:1588-1593, 2000[Abstract/Free Full Text]

50. Wiktor A, Rybicki BA, Piao ZS, et al: Clinical significance of Y chromosome loss in hematologic disease. Genes Chromosomes Cancer 27:11-16, 2000[CrossRef][Medline]

51. Freedman AS, Neuberg D, Mauch P, et al: Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 94:3325-3333, 1999[Abstract/Free Full Text]

52. Stiff PJ, Dahlberg S, Forman SJ, et al: Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: Value of augmented preparative regimens—A Southwest Oncology Group trial. J Clin Oncol 16:48-55, 1998[Abstract/Free Full Text]

53. Shipp MA, Abeloff MD, Antman KH, et al: International Consensus Conference on High-Dose Therapy With Hematopoietic Stem-Cell Transplantation in Aggressive Non-Hodgkin's Lymphomas: Report of the jury. J Clin Oncol 17:423-429, 1999[Free Full Text]

54. 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 316:1499-1505, 1987[Abstract]

55. Johnson TA, Press OW: Synergistic cytotoxicity of iodine-131-anti-CD20 monoclonal antibodies and chemotherapy for treatment of B-cell lymphomas. Int J Cancer 85:104-112, 2000[CrossRef][Medline]

56. Cohen H: Cancer and Aging. Am Soc Clin Oncol Ed Book 223-226, 1998

57. Centers for Disease Control and Prevention/National Center for Health Statistics Vital and Health Statistics: Trends in the Health of Older Americans, 1994. Atlanta, GA, Centers for Disease Control and Prevention/National Center for Health Statistics, 1994, pp 131-158

58. Yancik R: Population aging and cancer: A cross-national concern. Cancer J 11:437-441, 2005[Medline]

59. Sateren WB, Trimble EL, Abrams J, et al: How sociodemographics, presence of oncology specialists, and hospital cancer programs affect accrual to cancer treatment trials. J Clin Oncol 20:2109-2117, 2002[Abstract/Free Full Text]

60. Hutchins LF, Unger JM, Crowley JJ, et al: Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999[Abstract/Free Full Text]

Submitted September 26, 2006; accepted January 4, 2007.

This article has been cited by other articles:

				A. K. Gopal, O. W. Press, S. M. Wilbur, D. G. Maloney, and J. M. Pagel Rituximab blocks binding of radiolabeled anti-CD20 antibodies (Ab) but not radiolabeled anti-CD45 Ab Blood, August 1, 2008; 112(3): 830 - 835. [Abstract] [Full Text] [PDF]

				J. A. Thompson, R. I. Fisher, M. LeBlanc, S. J. Forman, O. W. Press, J. M. Unger, A. P. Nademanee, P. J. Stiff, S. H. Petersdorf, and A. Fefer Total body irradiation, etoposide, cyclophosphamide, and autologous peripheral blood stem-cell transplantation followed by randomization to therapy with interleukin-2 versus observation for patients with non-Hodgkin lymphoma: results of a phase 3 randomized trial by the Southwest Oncology Group (SWOG 9438) Blood, April 15, 2008; 111(8): 4048 - 4054. [Abstract] [Full Text] [PDF]

				B. S. Kahl New Therapeutic Strategies for Mantle Cell Lymphoma ASCO Educational Book, January 1, 2008; 2008(1): 392 - 397. [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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gopal, A. K. Articles by Press, O. W. Search for Related Content PubMed PubMed Citation Articles by Gopal, A. K. Articles by Press, O. W.