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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Clinical Research Division, Fred Hutchinson
Cancer Research Center, and the Department of Medicine, Division of
Medical Oncology, Department of Radiology, Division of Nuclear
Medicine, Department of Pathology, Department of Biostatistics, and
Department of Pediatrics, University of Washington, Seattle, WA.
Relapsed mantle cell lymphoma is a radiation-sensitive malignancy
that is unlikely to be cured by treatment with conventional high-dose
therapy and autologous stem cell transplantation. We tested the safety
and efficacy of using a CD20-specific monoclonal antibody conjugated
with 131I to deliver high-dose radiation selectively to all
lymphoma sites. Patients with relapsed or refractory mantle cell
lymphoma received infusions of 131I-labeled CD20-specific
monoclonal antibody (Tositumomab). The antibody dose was 1.7 mg/kg body
weight, and the amount of 131I was calibrated to deliver 20 to 25 Gy to vital normal organs. This treatment was followed 10 days
later by administration of high-dose etoposide (30-60 mg/kg),
cyclophosphamide (60-100 mg/kg), and infusion of cryopreserved
autologous stem cells. The 16 patients in this study had received a
median of 3 prior treatments, and 7 had chemotherapy-resistant disease.
The median dose of 131I was 510 mCi (18.87 GBq). There were
no therapy-related deaths. Among the 11 patients with conventionally
measurable disease at the time of treatment, the respective complete
and overall response rates were 91% and 100%. Fifteen patients
remain alive, and 12 have had no progression of lymphoma at 6 to
57 months from transplantation and 16 to 97 months from diagnosis.
Overall survival at 3 years from transplantation is estimated at 93%,
and progression-free survival is estimated at 61%. High-dose treatment
with 131I-Tositumomab, etoposide, and cyclophosphamide
results in a high remission rate and may provide long-term disease-free
survival for patients with relapsed or refractory mantle cell lymphoma.
(Blood. 2002;99:3158-3162) Mantle cell lymphoma (MCL) represents the second
most common aggressive non-Hodgkin lymphoma and affords one of the
greatest therapeutic challenges in hematologic oncology. This disease
characteristically displays adverse features of both indolent and
aggressive lymphomas, with short remission durations and few patients
experiencing long-term disease-free survival. From the time of
diagnosis, the duration of initial response is approximately 12 months,
and the median survival is approximately 32 months.1-4
Unlike other aggressive lymphomas, high-dose therapy with allogeneic or
autologous stem cell transplantation for relapsed or refractory disease
does not appear to provide durable remissions.5-10
The efficacy of standard high-dose therapy and autologous stem cell
transplantation is limited, in part, by the ability of normal
nonhematopoietic tissues to tolerate further dose escalation of
cytotoxic therapy. One approach to overcome this dose limitation is by
specifically targeting therapy to disease sites by means of
B-cell-specific (anti-CD20) monoclonal antibodies. We hypothesized that, based on the exquisite radiosensitivity of non-Hodgkin lymphoma, dose-escalated radiation to all tumor sites with the use of
CD20-targeted radioimmunotherapy may improve the remission durations
and survival of patients with relapsed MCL.11-13 Prior
studies have established the feasibility of delivering high-dose
CD20-targeted radioimmunotherapy and autologous stem cell
transplantation in other CD20-bearing B-cell
lymphomas.14-16 In this report we describe the efficacy of
high-dose chemo-radioimmunotherapy and autologous stem cell transplantation in the initial cohort of poor-risk, relapsed, or
chemotherapy refractory MCL patients.
Patient selection
Biodistribution studies
Therapeutic antibody and chemotherapy infusions Ten to 14 days after biodistribution studies, patients received therapeutic 131I-Tositumomab at a protein dose of 1.7 mg/kg body weight to deliver the calculated target dose to the normal organ receiving the highest dose. Patients remained in radiation isolation until radiation exposure was less than or equal to 0.07 mSv/hour (7 mR/hour) at 1 m (median, 10 days; range, 8-13 days). Patients were then treated with high-dose etoposide, followed 2 days later by high-dose cyclophosphamide. Patients were infused with autologous peripheral blood stem cells when radiation exposure was less than 0.02 mSv/hour (2 mR/hour) at 1 m. The overall treatment schema is summarized in Figure 1.
Toxicity evaluation Toxicity evaluation was classified according to the scale devised by Bearman et al.18 Toxicities on this scale were graded at grade III (life threatening) or grade IV (fatal). Toxicities not included in the Bearman Scale were evaluated by the National Cancer Institute Toxicity Scale.Evaluation of response and follow-up Response was determined in comparison to disease status after cytoreductive chemotherapy and stem cell collection. Complete response was defined as a resolution of all physical examination or radiographic evidence of tumor, including normalization of bone marrow by morphologic and flow cytometric criteria. Partial response was defined as a 50% or greater decrease in tumor size. The remaining patients were categorized as progression free if there was no evidence of progression (> 25% increase in size of tumor) at the 1-month posttreatment evaluation point. Patients with persistent evaluable but not bidimensional measurable disease and without evidence of blood or bone marrow involvement after cytoreductive therapy that remained unchanged after radioimmunotherapy were considered progression free. Computerized tomography evaluations were planned at 1, 3, 6, and 12 months after transplantation and annually thereafter. Bone marrow studies were performed at 1 month after therapy and annually thereafter whenever possible. Patients were clinically assessed more frequently at the discretion of the primary physician. Progression was defined as clinical, radiographic, bone marrow, flow cytometric, or molecular evidence of progressive disease, or administration of any antilymphoma therapy for suspected progression. Survival was estimated by the method of Kaplan and Meier.
Baseline patient information Sixteen consecutive patients with confirmed MCL were treated on sequential phase I and phase II trials designed for relapsed B-cell non-Hodgkin lymphomas. The clinical characteristics of these patients are detailed in Table 1. Thirteen patients (81%) were men, 4 (25%) had known gastrointestinal involvement, 2 (13%) had involvement of the orbit, and 1 patient had lymphomatous pulmonary infiltration. Thirteen patients had sufficient histologic specimens available to reconfirm the diagnosis of MCL in our own laboratories by characteristic cyclin D1 expression and/or translocation between chromosomes 11 and 14 by polymerase chain reaction (PCR). Patients underwent a median of 3 prior therapies (range, 2-7) and 9 prior cycles (range, 5-13) of chemotherapy with 88% and 31% receiving prior anthracycline-based and platinum-based regimens, respectively. The details of the prior therapy and responses are summarized in Table 2. In addition, 7 patients (44%) were refused for treatment by other major tertiary transplantation referral centers because of the perceived lack of efficacy of standard high-dose therapy and autologous stem cell transplantation for relapsed MCL, presence of chemotherapy refractory disease, or other high-risk features.
Treatment received Because patients were treated according to both phase I (dose-finding) and phase II trials, which also included patients with other types of B-cell lymphomas, not all MCL patients received identical doses of 131I-Tositumomab or chemotherapy. MCL patients received a median of 510 mCi (18.87 GBq) of 131I (range, 324-782 mCi, [11.99-29.94 GBq]). Although the physical half-life of 131I is 8 days, the median effective biologic half-time of 131I-Tositumomab was 73 hours (range, 45-86 hours) in these patients. Two patients received estimated absorbed radiation doses of 20 Gy and 23 Gy to the dose-limiting critical normal organ, and the remaining 14 patients received the maximally tolerated dose of 25 Gy. Likewise, 12 patients received 60 mg/kg etoposide along with 100 mg/kg cyclophosphamide, and 4 patients were treated with 30 mg/kg etoposide and 60 mg/kg cyclophosphamide. All patients were reinfused with autologous peripheral blood stem cells with 3 of the patients (19%) receiving CD34-selected stem cell products and 8 (50%) receiving products that were both CD34 selected and B-cell depleted with anti-CD20 and anti-CD19 antibodies. Three patients had molecular evidence of residual lymphomatous contamination of peripheral blood stem cells at the time of reinfusion with 2 of these 3 patients receiving CD34-selected and CD19/CD20-depleted stem cells and 1 receiving unmanipulated stem cells.Toxicity Overall, toxicities were comparable to standard autologous transplantation conditioning regimens. There was no treatment-related mortality. Toxicity experienced during radiation isolation was all less than grade 1, generally consisted of mild anorexia, and did not require entry of medical staff into the patient room. After transplantation one patient experienced reversible interstitial pneumonitis requiring temporary mechanical ventilation. Another patient who had received prior radiotherapy to lung fields also experienced delayed pneumonitis of grade II severity that responded to corticosteroid administration. All patients demonstrated expected myeloablation with a median time to neutrophil recovery ( 0.5 × 109/L) of 12 days (range,
9-19 days) after transplantation and a median time to unsupported
platelet count (20 × 109/L) of 12 days (range, 8-24 days) after transplantation. One patient who remains in remission has
developed delayed neutropenia and thrombocytopenia persisting for more
than 1 year after transplantation without evidence of myelodysplasia.
Response to therapy Eleven patients had disease that could be fully evaluated for response to the conditioning regimen, whereas 5 patients had minimal radiographically defined residual disease or only molecular evidence of disease at the time of transplantation. All 5 of these patients with minimal disease remained progression free at 1 month after transplantation and have remained progression free to date. Of the 11 patients with fully evaluable disease, 8 (73%) attained a complete response and 1 (9%) achieved a partial response at the initial 1-month posttransplantation evaluation, with the 2 nonresponding patients remaining progression free. One of these 2 evaluable patients who did not attain a remission had residual flow-cytometrically identified lymphoma involving the bone marrow at the 1-month point that became flow and morphologically negative at 3 months after transplantation. The second patient who had radiographically stable disease at the 1-month posttransplantation time point was radiographically in a complete remission at the 1-year follow-up. If these 2 initially progression-free patients are considered complete remissions, which they eventually achieved, the overall response rate among the 11 evaluable patients was 100%, with 91% attaining a complete response.Ten of 16 patients had molecular evidence of disease either by PCR detection of a characteristic translocation between chromosomes 11 and 14 (BCL-1) or immunoglobulin heavy chain clonality in blood or bone marrow immediately pretreatment after cytoreduction and peripheral blood stem cell collection. Five of these 10 patients attained molecular remission in both blood and bone marrow at the 1-month time point (50%). In addition, 1 of these 5 remaining PCR-positive patients had a molecular evaluation of blood and bone marrow at 1 year and has converted to PCR negativity. The overall molecular response to date is 60% in the 10 evaluable patients. Overall and progression-free survival Fifteen (94%) of 16 patients remain alive at the time of data analysis (July 6, 2001) with a median follow-up of 19 months (range, 6-57 months) from the time of transplantation and 49 months (range, 16-97 months) from time of diagnosis. In addition, 12 patients (75%) remain alive and progression free with 3 patients remaining alive and in remission 4 or more years after treatment. These data result in an estimated 3-year overall survival of 93% and an estimated 3-year progression-free survival of 61% (Figure 2). By univariate analysis, the chemotherapy dose; radiation dose; number of prior regimens; chemosensitivity at the time of transplantation; PCR status of patients' peripheral blood stem cells, blood, or bone marrow; elevated lactate dehydrogenase; or bulk of disease were not correlated with overall or progression-free survival, although the power of such an analysis is limited by sample size and low number of events (progression or death).
Our study is the first to demonstrate the potential clinical efficacy of supplanting total body radiation with high-dose radioimmunotherapy in an autologous transplantation conditioning regimen for patients with relapsed or refractory MCL. This favorable outcome is particularly unexpected in these patients who were heavily pretreated (9 of 16 received 3 or more prior therapies), commonly had an elevated lactate dehydrogenase at the time of transplantation (50%), and whose disease frequently was not responsive to their last regimen before transplantation (44%). These negative pretransplantation features have been associated with poor outcomes in other non-Hodgkin lymphoma subtypes in which the use of high-dose therapy and autologous stem cell transplantation has been more extensively evaluated.19-22 The apparent efficacy of this approach in MCL may be attributed to several potential mechanisms. In prior studies we evaluated radiation doses to tumor by biopsy and gamma counting of involved nodes after trace infusions. By using this methodology, we have been able to demonstrate on average 10:1 and 2 to 3:1 tumor-to-whole body and tumor-to-highest critical normal organ ratios of delivered radiation, respectively. This approach resulted in doses to tumor as high as 91.5 Gy.14 The persistent remissions of these high-risk patients correspond with the observation that lymphoma patients rarely relapse within sites previously treated with external beam radiation therapy, especially when doses above 30 to 40Gy are administered.11,12,23,24 The delayed remissions seen in 2 of 11 evaluable patients parallel our previous observations with high-dose radioimmunotherapy and may be related to the low radiation dose rates (centi-Gray per minute) of 131I-Tositumomab relative to total body irradiation or the effect of the antibody alone.25 The potential efficacy of this approach may be further augmented by the high surface density of the CD20 target antigen on nearly all cases of MCL.26 This increased antigen density could allow for a greater number of sites for antibody binding, further optimizing the targeted radioimmunotherapy. Finally, the observation that 9 of the 16 patients had progressive disease after prior unlabeled anti-CD20 therapy (rituximab) suggests that the major therapeutic activity of radioimmunotherapy is derived from the targeted radiation, rather than the effect of the antibody itself. In addition to the high response rate, we also observed molecular remissions in most of the patients remaining PCR positive despite pretransplantation cytoreductive therapy. Notably, the lack of correlation of progression-free survival with ability to attain PCR negativity may reflect the imprecision of the assay, the inability to fully assess the molecular status of nodal disease, or the small number of events on which to base an analysis. Longer follow-up, including repeat molecular analyses of the remaining 4 PCR-positive patients, will be necessary to determine the predictive role of molecular remissions when using high-dose radioimmunotherapy for MCL. Although the results of this trial are encouraging, the findings should not be extrapolated to subsets of patients who were excluded from this study. Patients with splenomegaly or tumor bulk more than 500 cc were excluded because of previous experience demonstrating that such patients would not have optimal biodistributions of antibody.14 Even though 2 individuals with splenomegaly had a splenectomy before enrollment, excluding patients with enlarged spleens or excessively bulky disease may have favorably skewed our results. However, patients with no detectable evidence of disease after their pretransplantation cytoreductive therapy were also excluded from this trial (because of the absence of a target for the radioimmunotherapy), thus excluding the patients most likely to have the best outcome. Other approaches have also been investigated to improve the outcome for patients with MCL. Encouraging results have come from the use of an aggressive multiagent acute lymphoblastic leukemialike induction therapy (HyperCVAD/HD MTX HDAC) followed by high-dose therapy and autologous or allogeneic stem cell transplantation in patients with newly diagnosed MCL.8 Unfortunately, this approach yielded an estimated 17% of previously treated patients similar to those in our study being event free at 3 years. Other groups have also observed similar results with little evidence of long-term remission for patients with relapsed/refractory disease by using standard high-dose therapy and autologous stem cell transplantation.5,6,9,10 In one large series all patients who had received 3 or more prior regimens relapsed by 14 months after transplantation.7 Our data provide the first suggestion that escalation of radiation therapy dose by means of a high-dose radioimmunotherapy-based transplantation-conditioning regimen may overcome the inherently poor prognosis of patients with relapsed or refractory MCL, potentially affording long-term remissions. Additional patients, further follow-up, and randomized trials will be needed to confirm the efficacy of this approach.
The technical expertise of Carolyn Thostenson and Bhavesha Patel is gratefully acknowledged. We also thank Corixa Pharmaceutical for providing Tositumomab antibody for these trials.
Submitted October 29, 2001; accepted December 28, 2001.
Support by National Institutes of Health grants P01CA44991 and K23CA85479 and by American Society of Clinical Oncology Young Investigator Award.
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: Ajay K. Gopal, Seattle Cancer Care Alliance, Mailstop G6-800 (Rm 6802), 825 Eastlake Ave E, Seattle, WA 98109; e-mail: agopal{at}u.washington.edu.
1. Hiddemann W, Unterhalt M, Herrmann R, et al. Mantle-cell lymphomas have more widespread disease and a slower response to chemotherapy compared with follicle-center lymphomas: results of a prospective comparative analysis of the German Low-Grade Lymphoma Study Group. J Clin Oncol. 1998;16:1922-1930[Abstract].
2.
Velders GA, Kluin-Nelemans JC, De Boer CJ, et al.
Mantle-cell lymphoma: a population-based clinical study.
J Clin Oncol.
1996;14:1269-1274 3. Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol. 1998;16:2780-2795[Abstract].
4.
Fisher RI, Dahlberg S, Nathwani BN, Banks PM, Miller TP, Grogan TM.
A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma (including the mucosa-associated lymphoid tissue and monocytoid B-cell subcategories): a Southwest Oncology Group study.
Blood.
1995;85:1075-1082
5.
Freedman AS, Neuberg D, Gribben JG, et al.
High-dose chemoradiotherapy and anti-B-cell monoclonal antibody-purged autologous bone marrow transplantation in mantle-cell lymphoma: no evidence for long-term remission.
J Clin Oncol.
1998;16:13-18
6.
Stewart DA, Vose JM, Weisenburger DD, et al.
The role of high-dose therapy and autologous hematopoietic stem cell transplantation for mantle cell lymphoma.
Ann Oncol.
1995;6:263-266 7. Vose JM, Bierman PJ, Weisenburger DD, et al. Autologous hematopoietic stem cell transplantation for mantle cell lymphoma. Biol Blood Marrow Transplant. 2000;6:640-645[CrossRef][Medline] [Order article via Infotrieve].
8.
Khouri IF, Romaguera J, Kantarjian H, et al.
Hyper-CVAD and high-dose methotrexate/cytarabine followed by stem-cell transplantation: an active regimen for aggressive mantle-cell lymphoma.
J Clin Oncol.
1998;16:3803-3809 9. Haas R, Brittinger G, Meusers P, et al. Myeloablative therapy with blood stem cell transplantation is effective in mantle cell lymphoma. Leukemia. 1996;10:1975-1979[Medline] [Order article via Infotrieve]. 10. Sohn SK, Bensinger W, Holmberg L, et al. High dose therapy with allogeneic or autologous stem cell transplantation for relapsed mantle cell lymphoma: the Seattle experience. Proc Am Soc Clin Oncol. 1998;17:17a. 11. Hallahan DE, Farah R, Vokes EE, et al. The patterns of failure in patients with pathological stage I and II diffuse histiocytic lymphoma treated with radiation therapy alone. Int J Radiat Oncol Biol Phys. 1989;17:767-771[Medline] [Order article via Infotrieve]. 12. Kaminski MS, Coleman CN, Colby TV, Cox RS, Rosenberg SA. Factors predicting survival in adults with stage I and II large-cell lymphoma treated with primary radiation therapy. Ann Intern Med. 1986;104:747-756.
13.
Mac Manus MP, Hoppe RT.
Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University.
J Clin Oncol.
1996;14:1282-1290
14.
Press OW, Eary JF, Appelbaum FR, et al.
Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support.
N Engl J Med.
1993;329:1219-1224 15. 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. 1995;346:336-340[CrossRef][Medline] [Order article via Infotrieve].
16.
Press OW, Eary JF, Gooley T, et al.
A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas.
Blood.
2000;96:2934-2942
17.
Eary JF, Press OW, Badger CC, et al.
Imaging and treatment of B-cell lymphoma.
J Nucl Med.
1990;31:1257-1268
18.
Bearman SI, Appelbaum FR, Buckner CD, et al.
Regimen-related toxicity in patients undergoing bone marrow transplantation.
J Clin Oncol.
1988;6:1562-1568 19. 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. 2001;27:593-599[CrossRef][Medline] [Order article via Infotrieve]. 20. Gulati S, Yahalom J, Acaba L, et al. Treatment of patients with relapsed and resistant non-Hodgkin's lymphoma using total body irradiation, etoposide, and cyclophosphamide and autologous bone marrow transplantation. J Clin Oncol. 1992;10:936-941[Abstract].
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.
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.
1999;17:423-429 23. Aref A, Narayan S, Tekyi-Mensah S, et al. Value of radiation therapy in the management of chemoresistant intermediate grade non-Hodgkin's lymphoma. Radiat Oncol Investig. 1999;7:186-191[CrossRef][Medline] [Order article via Infotrieve]. 24. Sutcliffe SB, Gospodarowicz MK, Bush RS, et al. Role of radiation therapy in localized non-Hodgkin's lymphoma. Radiother Oncol. 1985;4:211-223[Medline] [Order article via Infotrieve]. 25. 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]. 26. Ginaldi L, De Martinis M, Matutes E, Farahat N, Morilla R, Catovsky D. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol. 1998;51:364-369[Abstract].
© 2002 by The American Society of Hematology.
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  B. G. Till, M. C. Jensen, J. Wang, E. Y. Chen, B. L. Wood, H. A. Greisman, X. Qian, S. E. James, A. Raubitschek, S. J. Forman, et al. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells Blood, September 15, 2008; 112(6): 2261 - 2271. [Abstract] [Full Text] [PDF]
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|
 |
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 F. R. Appelbaum Hematopoietic Cell Transplantation for Non-Hodgkin's Lymphoma: Yesterday, Today, and Tomorrow J. Clin. Oncol., June 20, 2008; 26(18): 2927 - 2929. [Full Text] [PDF]
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 |
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 J. G. Rajendran, A. K. Gopal, D. R. Fisher, L. D. Durack, T. A. Gooley, and O. W. Press Myeloablative 131I-Tositumomab Radioimmunotherapy in Treating Non-Hodgkin's Lymphoma: Comparison of Dosimetry Based on Whole-Body Retention and Dose to Critical Organ Receiving the Highest Dose J. Nucl. Med., May 1, 2008; 49(5): 837 - 844. [Abstract] [Full Text] [PDF]
|
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 |
|
 C. Bodet-Milin, F. Kraeber-Bodere, B. Dupas, F. Morschhauser, T. Gastinne, S. Le Gouill, L. Campion, J.-L. Harousseau, W. A. Wegener, D. M. Goldenberg, et al. Evaluation of response to fractionated radioimmunotherapy with 90Y-epratuzumab in non-Hodgkin's lymphoma by 18F-fluorodeoxyglucose positron emission tomography Haematologica, March 1, 2008; 93(3): 390 - 397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Krishnan, A. Nademanee, H. C. Fung, A. A. Raubitschek, A. Molina, D. Yamauchi, R. Rodriguez, R. T. Spielberger, P. Falk, J. M. Palmer, et al. Phase II Trial of a Transplantation Regimen of Yttrium-90 Ibritumomab Tiuxetan and High-Dose Chemotherapy in Patients With Non-Hodgkin's Lymphoma J. Clin. Oncol., January 1, 2008; 26(1): 90 - 95. [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]
|
|
|
|
 |
|
 D. J. Straus How I Treat Mantle Cell Lymphoma J. Oncol. Pract, September 1, 2007; 3(5): 281 - 282. [Full Text] [PDF]
|
|
|
|
|
|
A. Nademanee, S. Forman, A. Molina, H. Fung, D. Smith, A. Dagis, C. Kwok, D. Yamauchi, A.-L. Anderson, P. Falk, 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, October 15, 2005; 106(8): 2896 - 2902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. Witzig Current Treatment Approaches for Mantle-Cell Lymphoma J. Clin. Oncol., September 10, 2005; 23(26): 6409 - 6414. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. E. Witzig, S. M. Geyer, I. Ghobrial, D. J. Inwards, R. Fonseca, P. Kurtin, S. M. Ansell, R. Luyun, P. J. Flynn, R. F. Morton, et al. Phase II Trial of Single-Agent Temsirolimus (CCI-779) for Relapsed Mantle Cell Lymphoma J. Clin. Oncol., August 10, 2005; 23(23): 5347 - 5356. [Abstract] [Full Text] [PDF]
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M. Dreyling, G. Lenz, E. Hoster, A. Van Hoof, C. Gisselbrecht, R. Schmits, B. Metzner, L. Truemper, M. Reiser, H. Steinhauer, 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, April 1, 2005; 105(7): 2677 - 2684. [Abstract] [Full Text] [PDF]
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G. Lenz, M. Dreyling, E. Hoster, B. Wormann, U. Duhrsen, B. Metzner, H. Eimermacher, A. Neubauer, H. Wandt, H. Steinhauer, et al. Immunochemotherapy With Rituximab and Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Significantly Improves Response and Time to Treatment Failure, But Not Long-Term Outcome in Patients With Previously Untreated Mantle |
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Abstract
Introduction
